{"gene":"IDO1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1998,"finding":"IDO-mediated tryptophan catabolism by trophoblasts and macrophages at the maternal-fetal interface is required to suppress maternal T-cell responses and prevent allogeneic fetal rejection; pharmacological inhibition of IDO with 1-methyltryptophan caused rapid rejection of allogeneic concepti in pregnant mice.","method":"Pharmacological inhibition in vivo (1-methyl-tryptophan treatment of pregnant mice) with fetal survival readout","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo genetic/pharmacological experiment with defined phenotypic readout; foundational paper with >2000 citations replicated widely","pmids":["9712583"],"is_preprint":false},{"year":2002,"finding":"A subset of human plasmacytoid dendritic cells (pDCs) constitutively expresses IDO and suppresses T-cell proliferation in vitro; IDO-positive APCs were identified by co-expression of CD123 and CCR6 surface markers.","method":"Flow cytometry cell-surface phenotyping, in vitro T-cell suppression assay with IDO-expressing DC subset","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — functional IDO activity linked to defined DC subset, replicated by multiple subsequent labs","pmids":["12228717"],"is_preprint":false},{"year":2002,"finding":"IDO-expressing dendritic cells suppress allogeneic T-cell proliferation by depleting tryptophan and producing kynurenine pathway metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid), which are directly cytotoxic to activated T, B, and NK cells but not DCs.","method":"Adenoviral IDO gene transduction of human DCs, in vitro mixed lymphocyte reactions, metabolite supplementation/rescue assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — reconstituted IDO activity in DCs with metabolite-level mechanistic dissection and rescue experiments","pmids":["12186837"],"is_preprint":false},{"year":2003,"finding":"Most human tumors constitutively express IDO, and IDO expression by immunogenic mouse tumor cells prevents T-cell accumulation at the tumor site and immune rejection; systemic IDO inhibition partially reverses this immune escape.","method":"IDO expression screening in human tumor samples; IDO transfection into mouse tumor cells; in vivo T-cell accumulation and tumor rejection assays with IDO inhibitor treatment","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — gain-of-function (IDO transfection) combined with pharmacological inhibition in vivo; foundational cancer-immunology discovery paper","pmids":["14502282"],"is_preprint":false},{"year":2004,"finding":"Mouse tumor-draining lymph nodes contain a subset of pDCs that constitutively express immunosuppressive levels of IDO; these pDCs potently suppress T-cell responses and adoptive transfer creates antigen-specific T-cell anergy prevented by IDO gene disruption or IDO inhibitor treatment.","method":"Flow cytometry, adoptive transfer, IDO knockout mice, in vitro suppression assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic (IDO KO) and pharmacological evidence combined with adoptive transfer functional readout","pmids":["15254595"],"is_preprint":false},{"year":2004,"finding":"Human bone marrow stromal cells (MSCs) express IDO upon IFN-γ stimulation and inhibit allogeneic T-cell responses through IDO-mediated tryptophan degradation; addition of excess tryptophan restores T-cell proliferation.","method":"IFN-γ stimulation of MSCs, IDO activity measurement (kynurenine production), mixed lymphocyte reactions with tryptophan rescue","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — functional IDO activity assay combined with substrate rescue experiment","pmids":["15001472"],"is_preprint":false},{"year":2005,"finding":"IDO expression is under genetic control of Bin1; Bin1 loss elevates IDO expression through STAT1- and NF-κB-dependent pathways, facilitating immune escape of oncogenically transformed cells; small-molecule IDO inhibitors cooperate with cytotoxic chemotherapy to cause regression of established tumors in MMTV-Neu breast cancer mice.","method":"Bin1 knockout mouse studies, STAT1/NF-κB pathway analysis, in vivo tumor regression with IDO inhibitor + chemotherapy combination","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (Bin1 KO) combined with defined downstream transcription factor pathway and in vivo pharmacological validation","pmids":["15711557"],"is_preprint":false},{"year":2005,"finding":"Prostaglandin E2 (PGE2) induces IDO mRNA expression in monocyte-derived DCs via the Gs-protein-coupled EP2 receptor and adenylate cyclase activation, but a second signal through TNF receptor or a TLR is required to activate IDO enzyme activity.","method":"Quantitative IDO mRNA, protein, and enzyme activity assays; pharmacological receptor antagonism; two-step stimulation dissection","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — orthogonal assays (mRNA, protein, enzymatic activity) with receptor-specific pharmacological dissection","pmids":["15947091"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of human IDO at 2.3 Å resolution reveals two α-helical domains flanking a heme group; mutagenesis shows no polar residue in the distal heme pocket is essential for activity, supporting a reaction mechanism where iron-bound dioxygen abstracts a proton from L-tryptophan; residues F226, F227, and R231 maintain shape complementarity for substrate positioning.","method":"X-ray crystallography of IDO-4-phenylimidazole/cyanide complex; active-site mutagenesis; substrate-binding affinity assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and catalytic mechanism validation","pmids":["16477023"],"is_preprint":false},{"year":2006,"finding":"IDO is nitrated and enzymatically inactivated by peroxynitrite; liquid chromatography/tandem MS identified Tyr15, Tyr345, and Tyr353 as nitration sites in recombinant IDO; Tyr15-to-Phe mutation significantly reduces nitration-dependent inactivation, establishing Tyr15 as the critical residue.","method":"Peroxynitrite treatment of immunoprecipitated and recombinant IDO, nitrotyrosine detection by immunoprecipitation and LC/ESI-MS/MS, Tyr15Phe mutagenesis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzyme inactivation with mass-spectrometric site identification and site-directed mutagenesis validation","pmids":["16365430"],"is_preprint":false},{"year":2007,"finding":"MSCs inhibit IL-2-induced NK-cell proliferation, cytotoxic activity, cytokine production, and down-regulation of activating NK receptors (NKp30, NKp44, NKG2D) through IDO and prostaglandin E2 as key mediators.","method":"MSC/NK cell co-culture, IDO inhibitor (1-methyl-tryptophan) and COX inhibitor treatment, flow cytometry of NK receptor expression","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibitor dissection with multiple functional readouts (proliferation, cytotoxicity, receptor expression)","pmids":["17951526"],"is_preprint":false},{"year":2008,"finding":"IDO expression in plasmacytoid dendritic cells is induced by IFN-γ and is required for pDC-driven generation of inducible FoxP3+ regulatory T cells from CD4+CD25- T cells; kynurenine (the immediate IDO metabolite) bypasses IDO inhibition and restores Treg generation, implicating kynurenine production as the critical downstream mediator.","method":"TLR9 stimulation of human pDCs, IDO inhibitor (1-methyl-D-tryptophan) blocking, kynurenine supplementation rescue, Treg suppressor function assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — pharmacological inhibition combined with metabolite rescue in a defined cellular system","pmids":["18832696"],"is_preprint":false},{"year":2009,"finding":"TLR ligation on human bone marrow-derived MSCs enhances IDO1-dependent immunosuppression through an autocrine IFN-β signaling loop dependent on protein kinase R (PKR), but independent of IFN-γ.","method":"TLR ligand stimulation of MSCs, IFN-β neutralization, PKR pharmacological inhibition, IDO1 activity measurement (kynurenine production)","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of PKR/IFN-β/IDO1 axis with multiple inhibitor approaches","pmids":["19353519"],"is_preprint":false},{"year":2010,"finding":"Progressive HIV disease induces IDO1 in myeloid antigen-presenting DCs, and IDO1-derived 3-hydroxyanthranilic acid directly mediates loss of Th17 cells and reciprocal increase of Treg cells; this imbalance correlates with microbial translocation and sustained inflammation.","method":"HIV patient samples (blood and biopsies), in vitro IDO inhibitor experiments, addition of specific tryptophan catabolites to T-cell cultures with Th17/Treg readout","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — specific catabolite (3-hydroxyanthranilic acid) identified as direct mediator via in vitro reconstitution, corroborated by clinical samples","pmids":["20484731"],"is_preprint":false},{"year":2012,"finding":"Brain IDO1 upregulation in hippocampus mediates comorbidity of pain and depression; chronic pain induces IDO1 expression via IL-6/JAK/STAT pathway, increasing the kynurenine/tryptophan ratio and decreasing serotonin/tryptophan ratio; IDO1 knockout or pharmacological inhibition attenuates both nociceptive and depressive behavior.","method":"Rat chronic pain model, intra-hippocampal IL-6 injection, IDO1 KO mice, pharmacological IDO1 inhibition, HPLC metabolite measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic (KO) and pharmacological approaches with defined molecular pathway (IL-6/JAK/STAT → IDO1) and multiple behavioral/biochemical readouts","pmids":["22751107"],"is_preprint":false},{"year":2013,"finding":"IDO expression in the tumor microenvironment is driven by CD8+ T cells via IFN-γ signaling; PD-L1 and Treg recruitment also depend on intratumoral CD8+ T cells, revealing IDO as a T-cell-induced negative feedback mechanism rather than a pre-existing tumor escape program.","method":"Murine tumor models with T-cell depletion and IFN-γ neutralization; correlation of CD8+ T-cell presence with IDO expression in human tumors","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic depletion experiments in vivo establishing upstream regulatory dependence on CD8+ T cells and IFN-γ","pmids":["23986400"],"is_preprint":false},{"year":2013,"finding":"IDO is a critical resistance mechanism to anti-CTLA-4 immunotherapy; IDO knockout mice show striking tumor growth delay and improved survival with anti-CTLA-4 treatment; IDO inhibitors synergize with anti-CTLA-4, anti-PD-1, and anti-GITR antibodies by enhancing effector T-cell infiltration and increasing effector-to-Treg ratios in tumors.","method":"IDO knockout mouse tumor models, IDO inhibitor + immune checkpoint antibody combination experiments, flow cytometry of tumor-infiltrating immune cells","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic (IDO KO) combined with pharmacological approach with multiple immunological readouts","pmids":["23752227"],"is_preprint":false},{"year":2014,"finding":"IDO1 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, upon phosphorylation, act as docking sites for signaling partners including SHP-1 phosphatase and PI3K p110; this non-enzymatic signaling function activates the non-canonical NF-κB pathway in pDCs and induces long-lasting autocrine TGF-β production and immunosuppressive phenotype, independent of tryptophan catabolism.","method":"Transfection of NOD pDCs with IDO1 constructs, NF-κB pathway analysis, TGF-β measurement, cytokine production assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — reconstitution of IDO1 signaling function in deficient cells with defined pathway (ITIM phosphorylation → SHP-1/PI3K → non-canonical NF-κB → TGF-β) and multiple readouts","pmids":["25215657"],"is_preprint":false},{"year":2015,"finding":"IDO expressed by tumor cells recruits and activates myeloid-derived suppressor cells (MDSCs) through a mechanism dependent on regulatory T cells (Tregs); IDO inhibition in vivo reverses immunosuppression by decreasing tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function.","method":"Syngeneic tumor models with IDO-expressing tumor cells, IDO inhibitor treatment in vivo, flow cytometry of MDSC/Treg populations, functional suppression assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of IDO-Treg-MDSC axis with pharmacological intervention and multiple cellular readouts","pmids":["26411680"],"is_preprint":false},{"year":2016,"finding":"IFN-γ-induced IDO expression in DCs initiates an autocrine IDO-kynurenine/AhR-IDO positive feedback loop that maintains long-term IDO expression independent of exogenous IFN-γ; both IDO enzymatic activity and AhR expression are required for sustained IDO transcription, and kynurenine added to IDO-inhibited DC cultures restores IDO expression only in AhR-expressing DCs.","method":"In vitro DC stimulation with IFN-γ/CD40L, IDO inhibitor treatment, kynurenine supplementation rescue, AhR-deficient DC comparison, in vivo validation in tumor-bearing mice","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of autocrine feedback loop using pharmacological blockade and AhR-deficient cells with both in vitro and in vivo validation","pmids":["27316681"],"is_preprint":false},{"year":2017,"finding":"IDO expression in lung parenchyma is induced by IFN-γ from donor CD4+ T cells early after allogeneic hematopoietic stem cell transplantation; loss of IDO (gene deletion or IFN-γ blockade) results in acute lethal pulmonary inflammation (idiopathic pneumonia syndrome); IL-6 can induce IDO in an IFN-γ-independent manner when STAT3 deacetylation is inhibited; IDO-derived kynurenine suppresses inflammatory activity of lung epithelial cells and CD4+ T cells through the AhR pathway.","method":"IDO gene knockout mice, IFN-γ gene knockout donor T cells, HDAC inhibitor treatment, FK506 immunosuppression model, in vitro IL-6/STAT3/IDO pathway analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic models combined with pharmacological interventions, with defined cytokine pathways and AhR downstream signaling","pmids":["28673995"],"is_preprint":false},{"year":2019,"finding":"IDO1 inhibition mechanisms were characterized for multiple inhibitor classes; X-ray structure of the 1,2,3-triazole inhibitor MMG-0358 bound to IDO1 was determined; inhibitors were classified into mechanistic categories based on their mode of binding to the active site heme iron and surrounding residues.","method":"X-ray crystallography of IDO1-inhibitor complexes, enzyme kinetics, computational modeling","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with functional kinetic validation","pmids":["31525930"],"is_preprint":false},{"year":2020,"finding":"Under conditions favoring signaling rather than catabolic activity, IDO1 shifts from the cytosol to early endosomes; this subcellular translocation requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated and are required for full expression of the IDO1-dependent immunoregulatory phenotype in pDCs in vivo.","method":"Live-cell imaging, subcellular fractionation, PI3K inhibitors, in vivo pDC functional assays","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization experiment linked to functional consequence with pharmacological PI3K inhibition and in vivo validation","pmids":["33159421"],"is_preprint":false},{"year":2021,"finding":"Non-enzymatic (signaling) IDO1 activity in GBM tumor cells increases complement factor H (CFH) and its isoform FHL-1 expression independent of tryptophan metabolism; elevated CFH/FHL-1 increases tumor-infiltrating Tregs and MDSCs while decreasing CD8+ T cells and overall survival.","method":"IDO1 enzyme-null mutant reconstitution in GBM cell lines, microarray transcriptomic analysis, syngeneic and humanized mouse models, ex vivo co-culture assays","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — IDO1 catalytically-dead mutant reconstitution identifies non-enzymatic function with defined molecular target (CFH/FHL-1) validated in multiple in vivo models","pmids":["34479957"],"is_preprint":false},{"year":2022,"finding":"USP14, a proteasome-associated deubiquitinating enzyme, stabilizes IDO1 protein post-translationally; USP14 overexpression promotes tryptophan metabolism and T-cell dysfunction; knockdown or pharmacological inhibition of USP14 decreases IDO1 expression and reverses T-cell suppression in a syngeneic mouse model.","method":"Co-immunoprecipitation, ubiquitination assays, USP14 knockdown/pharmacological inhibition, MC38 syngeneic mouse model with anti-PD-1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — Co-IP identifying deubiquitinase-substrate relationship combined with in vitro and in vivo functional validation","pmids":["36163134"],"is_preprint":false},{"year":2023,"finding":"The non-enzymatic (signaling) function of IDO1 in B16-F10 melanoma tumor cells accelerates tumor cell proliferation through increased Ras and Erk activities, reduces CD8+ T-cell tumor infiltration, and increases FoxP3+ Treg infiltration; a catalytically-dead IDO1 mutant (H350A) that retains signaling capacity reproduces these effects both in vitro and in vivo.","method":"IDO1 wild-type and catalytic mutant (H350A) transfection into B16-F10 cells, Ras/Erk activity assays, syngeneic in vivo tumor models, flow cytometry of tumor-infiltrating lymphocytes","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 1–2 — catalytically-dead mutant isolates non-enzymatic function with defined signaling pathway (Ras/Erk) and in vivo immune infiltrate readout","pmids":["36733497"],"is_preprint":false},{"year":2023,"finding":"The IDO1 catalytic inhibitor epacadostat enhances the non-enzymatic (signaling/ITIM-mediated) immunosuppressive function of IDO1, providing a mechanistic explanation for its clinical failure; blocking enzymatic activity alone may be insufficient if signaling function is simultaneously potentiated.","method":"ITIM phosphorylation assays, signaling pathway analysis in IDO1-expressing immune cells treated with epacadostat, comparison of enzymatic vs. signaling IDO1 outputs","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — single laboratory study linking epacadostat to enhanced ITIM signaling, mechanistic but not yet independently replicated","pmids":["37122718"],"is_preprint":false},{"year":2021,"finding":"IDO1 contains two ITIM motifs that, when phosphorylated, recruit SHP-1 and PI3K p110 to trigger immunosuppressive signaling independent of catalytic activity; this non-enzymatic function reprograms immune cell gene expression toward an immunoregulatory phenotype.","method":"ITIM mutant constructs, phosphorylation assays, SHP-1/PI3K co-immunoprecipitation, gene expression profiling","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (mutagenesis, co-IP, gene expression) establishing ITIM-mediated signaling mechanism, corroborated by multiple studies from different labs","pmids":["34145969"],"is_preprint":false},{"year":2021,"finding":"The IDO1/kynurenine axis mediates hypoxic preconditioning-induced renoprotection; IDO1 deficiency abolishes systemic kynurenine increase and renoprotection from ischemia; exogenous kynurenine restores protection in Ido1-deficient mice, and kynurenine biotransformation preserves NAD+ in post-ischemic kidney.","method":"IDO1 knockout mice, serum metabolomics, pharmacological PHD inhibition, exogenous kynurenine administration, kidney ischemia-reperfusion model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic (Ido1 KO) combined with metabolomics and metabolite rescue experiment, establishing IDO1 as necessary and sufficient via kynurenine","pmids":["34407414"],"is_preprint":false}],"current_model":"IDO1 is a heme-containing dioxygenase that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine via a mechanism in which iron-bound dioxygen abstracts a proton from the substrate (established by crystal structure and mutagenesis); beyond its enzymatic function, phosphorylated ITIM motifs in IDO1 recruit SHP-1 and PI3K to drive non-canonical NF-κB signaling and long-lasting immunosuppression independent of tryptophan catabolism; IDO1 is induced primarily by IFN-γ (and secondarily by IL-6, TLR ligands, and PGE2 via EP2/cAMP signaling) in dendritic cells, MSCs, and tumor cells, where it depletes tryptophan and generates immunosuppressive kynurenines that induce T-cell apoptosis and anergy, shift the Th17/Treg balance, and recruit MDSCs; a kynurenine–AhR autocrine loop maintains long-term IDO1 expression in tolerogenic DCs; IDO1 protein stability is regulated post-translationally by USP14-mediated deubiquitination and is inactivated by peroxynitrite-mediated nitration of Tyr15; under signaling conditions IDO1 translocates from cytosol to early endosomes in a PI3K-dependent manner; and both its enzymatic and non-enzymatic functions contribute independently to tumor immune escape."},"narrative":{"teleology":[{"year":1998,"claim":"The question of whether tryptophan catabolism serves an immunoregulatory role in vivo was answered when pharmacological IDO inhibition caused rapid rejection of allogeneic fetuses, establishing IDO-mediated tryptophan depletion as a mechanism of maternal-fetal immune tolerance.","evidence":"1-methyl-tryptophan treatment of pregnant mice with allogeneic fetal survival readout","pmids":["9712583"],"confidence":"High","gaps":["Mechanism of T-cell suppression (depletion vs. metabolite toxicity) not resolved","Relative contribution of IDO vs. other tolerance mechanisms at the fetal-maternal interface unclear"]},{"year":2002,"claim":"The cellular mechanism by which IDO suppresses immunity was established: IDO-expressing dendritic cells inhibit T-cell proliferation both by depleting tryptophan and by producing cytotoxic kynurenine metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid), with a constitutively IDO-positive plasmacytoid DC subset identified as a key immunosuppressive population.","evidence":"Adenoviral IDO transduction of DCs with metabolite rescue assays; flow cytometry identification of IDO+ pDC subset with in vitro suppression","pmids":["12186837","12228717"],"confidence":"High","gaps":["Relative contribution of tryptophan depletion vs. kynurenine toxicity in vivo not quantified","Signaling pathways in T cells responding to tryptophan starvation not defined"]},{"year":2003,"claim":"Whether tumor cells exploit IDO for immune escape was directly tested: most human tumors constitutively express IDO, IDO-transfected tumor cells prevent T-cell accumulation and rejection, and tumor-draining lymph node pDCs use IDO to induce antigen-specific T-cell anergy.","evidence":"IDO expression screening in human tumors; IDO gain-of-function in mouse tumor lines; IDO-KO mice and adoptive transfer in tumor-draining LN pDC system","pmids":["14502282","15254595"],"confidence":"High","gaps":["Whether IDO-mediated anergy is reversible in established tumors not determined","Cell-intrinsic tumor-promoting effects of IDO not explored"]},{"year":2005,"claim":"Transcriptional regulation of IDO was delineated: Bin1 loss elevates IDO via STAT1/NF-κB, and PGE2 induces IDO mRNA through EP2/adenylate cyclase but requires a second TLR/TNF signal for enzymatic activation, revealing that IDO induction is a multi-signal integration point.","evidence":"Bin1-KO mouse analysis with STAT1/NF-κB pathway dissection; receptor-specific pharmacological antagonism with two-step stimulation protocol in DCs","pmids":["15711557","15947091"],"confidence":"High","gaps":["Post-transcriptional regulatory mechanisms not yet characterized","Relative dominance of IFN-γ vs. PGE2 induction in specific tissue contexts undefined"]},{"year":2006,"claim":"The catalytic mechanism and post-translational vulnerability of IDO1 were resolved: the 2.3 Å crystal structure showed two α-helical domains flanking a heme group with iron-bound dioxygen abstracting a proton from tryptophan, and peroxynitrite-mediated nitration of Tyr15 was identified as a specific inactivation mechanism.","evidence":"X-ray crystallography with active-site mutagenesis; LC/ESI-MS/MS nitration site mapping with Y15F mutant rescue","pmids":["16477023","16365430"],"confidence":"High","gaps":["Full catalytic cycle intermediates not captured crystallographically","Physiological relevance of peroxynitrite inactivation in specific tissues not established"]},{"year":2008,"claim":"The downstream immunological consequence of kynurenine was specified: IDO-expressing pDCs drive generation of FoxP3+ regulatory T cells, and kynurenine itself is sufficient to rescue Treg induction when IDO is pharmacologically blocked.","evidence":"TLR9-stimulated human pDCs with IDO inhibitor blocking and kynurenine rescue; Treg suppressor function assays","pmids":["18832696"],"confidence":"High","gaps":["Kynurenine receptor or sensor on T cells (later identified as AhR) not defined in this study","Relative contribution of different kynurenine catabolites to Treg generation not resolved"]},{"year":2010,"claim":"The specific kynurenine metabolite mediating Th17/Treg imbalance was identified as 3-hydroxyanthranilic acid, directly linking IDO1 enzymatic output to loss of Th17 cells and reciprocal Treg expansion in progressive HIV infection.","evidence":"HIV patient samples combined with in vitro addition of specific tryptophan catabolites to T-cell cultures","pmids":["20484731"],"confidence":"High","gaps":["Whether therapeutic IDO inhibition can restore Th17/Treg balance in HIV not tested","Contribution of other kynurenine metabolites to T-cell subset effects not fully dissected"]},{"year":2013,"claim":"IDO was repositioned from a pre-existing tumor escape mechanism to an adaptive feedback response: intratumoral CD8+ T cells drive IDO expression via IFN-γ, and IDO is a critical resistance mechanism to anti-CTLA-4 therapy, as IDO-KO mice show striking synergy with checkpoint blockade.","evidence":"T-cell depletion and IFN-γ neutralization in murine tumor models; IDO-KO mice treated with anti-CTLA-4/anti-PD-1/anti-GITR","pmids":["23986400","23752227"],"confidence":"High","gaps":["Whether IDO inhibitor + checkpoint blockade synergy translates to human tumors not established","Relative importance of tumor-cell vs. host-cell IDO not resolved"]},{"year":2014,"claim":"A non-enzymatic signaling function of IDO1 was discovered: phosphorylated ITIM motifs recruit SHP-1 and PI3K p110, activating non-canonical NF-κB and autocrine TGF-β production independent of tryptophan catabolism, establishing IDO1 as a dual-function protein.","evidence":"ITIM mutant and wild-type IDO1 reconstitution in NOD pDCs with NF-κB pathway analysis and TGF-β measurement","pmids":["25215657"],"confidence":"High","gaps":["Kinase responsible for ITIM phosphorylation not identified","Structural basis for ITIM-mediated signaling complex assembly unknown"]},{"year":2016,"claim":"How IDO expression is maintained long-term without sustained IFN-γ was explained by an autocrine kynurenine–AhR–IDO1 positive feedback loop in DCs, requiring both IDO enzymatic activity and AhR expression for sustained IDO transcription.","evidence":"IFN-γ/CD40L-stimulated DCs with IDO inhibitor, kynurenine rescue, and AhR-deficient DC comparison, validated in tumor-bearing mice","pmids":["27316681"],"confidence":"High","gaps":["Whether the kynurenine-AhR loop operates identically in tumor cells vs. DCs not shown","Chromatin-level mechanism of AhR-driven IDO1 transcription not defined"]},{"year":2020,"claim":"The subcellular dynamics of IDO1 signaling function were resolved: under signaling-favoring conditions IDO1 translocates from cytosol to early endosomes in a PI3K-dependent manner, and this relocalization is required for full immunoregulatory function of pDCs in vivo.","evidence":"Live-cell imaging, subcellular fractionation, PI3K inhibitors, and in vivo pDC functional assays","pmids":["33159421"],"confidence":"High","gaps":["Cargo/adaptor mediating IDO1 endosomal targeting not identified","Whether endosomal IDO1 retains catalytic activity or is exclusively signaling-competent unknown"]},{"year":2021,"claim":"The non-enzymatic function was shown to have distinct molecular outputs in tumors: catalytically dead IDO1 upregulates complement factor H/FHL-1 in GBM cells and activates Ras/Erk in melanoma cells, each independently promoting immune evasion and tumor growth.","evidence":"Catalytically dead (H350A) IDO1 mutant reconstitution in GBM and B16-F10 cell lines with syngeneic and humanized mouse models","pmids":["34479957","36733497"],"confidence":"High","gaps":["Signaling intermediates between ITIM phosphorylation and Ras/Erk or CFH upregulation not mapped","Whether non-enzymatic outputs are tissue/tumor-type specific not systematically tested"]},{"year":2022,"claim":"Post-translational stability regulation of IDO1 was identified: USP14 deubiquitinates IDO1, preventing its proteasomal degradation; USP14 inhibition reduces IDO1 protein levels and reverses T-cell suppression, synergizing with anti-PD-1 therapy.","evidence":"Co-immunoprecipitation, ubiquitination assays, USP14 knockdown/pharmacological inhibition in MC38 syngeneic mouse model","pmids":["36163134"],"confidence":"High","gaps":["E3 ubiquitin ligase targeting IDO1 for degradation not identified","Whether other deubiquitinases also regulate IDO1 stability not explored"]},{"year":2023,"claim":"The clinical failure of the IDO1 catalytic inhibitor epacadostat was mechanistically explained: epacadostat enhances ITIM-mediated non-enzymatic signaling function, potentially potentiating immunosuppression while blocking catalysis.","evidence":"ITIM phosphorylation assays and signaling pathway analysis in IDO1-expressing cells treated with epacadostat","pmids":["37122718"],"confidence":"Medium","gaps":["Not independently replicated","In vivo validation of enhanced signaling by epacadostat not shown","Whether next-generation inhibitors can block both functions simultaneously not tested"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase(s) that phosphorylate IDO1 ITIMs, the E3 ubiquitin ligase opposing USP14-mediated stabilization, how non-enzymatic signaling outputs differ across tissue and tumor contexts, and whether dual-function (catalytic + signaling) IDO1 inhibitors can achieve clinical immunotherapeutic efficacy.","evidence":"","pmids":[],"confidence":"High","gaps":["ITIM kinase identity unknown","E3 ligase for IDO1 ubiquitination not identified","No dual-function inhibitor validated in clinical models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,8,9,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[17,22,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[17,23,25,27]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[22]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[22]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,3,4,11,15,16,17,18,27]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,8,13,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,22,25,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,6,16,23,25]}],"complexes":[],"partners":["SHP-1","PIK3CA","USP14","AHR","BIN1"],"other_free_text":[]},"mechanistic_narrative":"IDO1 is a heme-containing dioxygenase that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine, functioning as a central node of immune regulation by depleting tryptophan and generating immunosuppressive kynurenine-pathway metabolites that induce T-cell apoptosis, promote FoxP3+ regulatory T-cell differentiation, shift the Th17/Treg balance, and recruit myeloid-derived suppressor cells [PMID:12186837, PMID:18832696, PMID:20484731, PMID:26411680]. Its crystal structure reveals two α-helical domains flanking an active-site heme, with iron-bound dioxygen abstracting a proton from L-tryptophan; enzyme activity is induced primarily by IFN-γ (and by IL-6, TLR ligands, and PGE2 via EP2/cAMP), and is sustained through an autocrine kynurenine–AhR positive-feedback loop in dendritic cells [PMID:16477023, PMID:15947091, PMID:27316681]. Beyond catalysis, phosphorylated ITIM motifs in IDO1 recruit SHP-1 and PI3K to activate non-canonical NF-κB signaling and long-lasting immunosuppression independent of tryptophan catabolism; catalytically dead mutants retain the ability to promote tumor immune evasion via Ras/Erk activation, complement factor H upregulation, and altered tumor-infiltrating lymphocyte composition [PMID:25215657, PMID:34145969, PMID:34479957, PMID:36733497]. IDO1 protein stability is regulated by USP14-mediated deubiquitination, and the enzyme is inactivated by peroxynitrite-mediated nitration of Tyr15; under signaling-favoring conditions IDO1 translocates from the cytosol to early endosomes in a PI3K-dependent manner [PMID:36163134, PMID:16365430, PMID:33159421]."},"prefetch_data":{"uniprot":{"accession":"P14902","full_name":"Indoleamine 2,3-dioxygenase 1","aliases":["Indoleamine-pyrrole 2,3-dioxygenase"],"length_aa":403,"mass_kda":45.3,"function":"Catalyzes the first and rate limiting step of the catabolism of the essential amino acid tryptophan along the kynurenine pathway (PubMed:17671174, PubMed:18026683). Involved in the peripheral immune tolerance, contributing to maintain homeostasis by preventing autoimmunity or immunopathology that would result from uncontrolled and overreacting immune responses (PubMed:25691885). Tryptophan shortage inhibits T lymphocytes division and accumulation of tryptophan catabolites induces T-cell apoptosis and differentiation of regulatory T-cells (PubMed:25691885). Acts as a suppressor of anti-tumor immunity (PubMed:14502282, PubMed:23103127, PubMed:25157255, PubMed:25691885). Limits the growth of intracellular pathogens by depriving tryptophan (PubMed:25691885). Protects the fetus from maternal immune rejection (PubMed:25691885)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P14902/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IDO1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IDO1","total_profiled":1310},"omim":[{"mim_id":"612129","title":"INDOLEAMINE 2,3-DIOXYGENASE 2; IDO2","url":"https://www.omim.org/entry/612129"},{"mim_id":"600253","title":"ARYL HYDROCARBON RECEPTOR; AHR","url":"https://www.omim.org/entry/600253"},{"mim_id":"191070","title":"TRYPTOPHAN 2,3-DIOXYGENASE; TDO2","url":"https://www.omim.org/entry/191070"},{"mim_id":"147435","title":"INDOLEAMINE 2,3-DIOXYGENASE; IDO1","url":"https://www.omim.org/entry/147435"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Microtubules","reliability":"Approved"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":55.0},{"tissue":"placenta","ntpm":104.2}],"url":"https://www.proteinatlas.org/search/IDO1"},"hgnc":{"alias_symbol":[],"prev_symbol":["IDO","INDO"]},"alphafold":{"accession":"P14902","domains":[{"cath_id":"1.20.58.480","chopping":"7-359_371-396","consensus_level":"medium","plddt":94.9948,"start":7,"end":396}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14902","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14902-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14902-F1-predicted_aligned_error_v6.png","plddt_mean":93.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IDO1","jax_strain_url":"https://www.jax.org/strain/search?query=IDO1"},"sequence":{"accession":"P14902","fasta_url":"https://rest.uniprot.org/uniprotkb/P14902.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14902/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14902"}},"corpus_meta":[{"pmid":"15459668","id":"PMC_15459668","title":"IDO expression by dendritic cells: tolerance and tryptophan catabolism.","date":"2004","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15459668","citation_count":1836,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26839260","id":"PMC_26839260","title":"IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance.","date":"2016","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26839260","citation_count":808,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23090118","id":"PMC_23090118","title":"Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23090118","citation_count":575,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26411680","id":"PMC_26411680","title":"Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26411680","citation_count":397,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29254698","id":"PMC_29254698","title":"Targeting the IDO1/TDO2-KYN-AhR Pathway for Cancer Immunotherapy - Challenges and Opportunities.","date":"2017","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29254698","citation_count":390,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30068361","id":"PMC_30068361","title":"Targeting the IDO1 pathway in cancer: from bench to bedside.","date":"2018","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30068361","citation_count":356,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25628622","id":"PMC_25628622","title":"Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors.","date":"2015","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25628622","citation_count":298,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33883013","id":"PMC_33883013","title":"Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33883013","citation_count":280,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26519060","id":"PMC_26519060","title":"Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/26519060","citation_count":268,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18317452","id":"PMC_18317452","title":"Immune escape as a fundamental trait of cancer: focus on IDO.","date":"2008","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/18317452","citation_count":260,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36058143","id":"PMC_36058143","title":"Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy.","date":"2022","source":"Cancer treatment reviews","url":"https://pubmed.ncbi.nlm.nih.gov/36058143","citation_count":227,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25941578","id":"PMC_25941578","title":"Trial watch: IDO inhibitors in cancer therapy.","date":"2014","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/25941578","citation_count":190,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24184687","id":"PMC_24184687","title":"Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis.","date":"2013","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24184687","citation_count":186,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33072086","id":"PMC_33072086","title":"IDO Expression in Cancer: Different Compartment, Different Functionality?","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33072086","citation_count":172,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32612606","id":"PMC_32612606","title":"Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32612606","citation_count":170,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25970480","id":"PMC_25970480","title":"Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.","date":"2015","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25970480","citation_count":170,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34145969","id":"PMC_34145969","title":"Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme.","date":"2021","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/34145969","citation_count":163,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28751450","id":"PMC_28751450","title":"Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/28751450","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32934882","id":"PMC_32934882","title":"Trial watch: IDO inhibitors in cancer therapy.","date":"2020","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/32934882","citation_count":153,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36163134","id":"PMC_36163134","title":"USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36163134","citation_count":151,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32194572","id":"PMC_32194572","title":"IDO and Kynurenine Metabolites in Peripheral and CNS Disorders.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32194572","citation_count":151,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29413421","id":"PMC_29413421","title":"Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'.","date":"2017","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/29413421","citation_count":145,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35085834","id":"PMC_35085834","title":"Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process.","date":"2022","source":"Ageing research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/35085834","citation_count":144,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25157255","id":"PMC_25157255","title":"New Insights into IDO Biology in Bacterial and Viral Infections.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25157255","citation_count":136,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27316681","id":"PMC_27316681","title":"Tolerogenic Phenotype of IFN-γ-Induced IDO+ Dendritic Cells Is Maintained via an Autocrine IDO-Kynurenine/AhR-IDO Loop.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27316681","citation_count":120,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17202379","id":"PMC_17202379","title":"IL-8 and IDO expression by human gingival fibroblasts via TLRs.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17202379","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32296044","id":"PMC_32296044","title":"Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway.","date":"2020","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32296044","citation_count":113,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31315643","id":"PMC_31315643","title":"A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31315643","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34479957","id":"PMC_34479957","title":"Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma.","date":"2021","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/34479957","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19494274","id":"PMC_19494274","title":"The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/19494274","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34284200","id":"PMC_34284200","title":"Indoleamine 2,3-dioxygenase (Ido) inhibitors and their nanomedicines for cancer immunotherapy.","date":"2021","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/34284200","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29473428","id":"PMC_29473428","title":"A patent review of IDO1 inhibitors for cancer.","date":"2018","source":"Expert opinion on therapeutic patents","url":"https://pubmed.ncbi.nlm.nih.gov/29473428","citation_count":92,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31286779","id":"PMC_31286779","title":"Nanoenabled Reversal of IDO1-Mediated Immunosuppression Synergizes with Immunogenic Chemotherapy for Improved Cancer Therapy.","date":"2019","source":"Nano letters","url":"https://pubmed.ncbi.nlm.nih.gov/31286779","citation_count":89,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16166276","id":"PMC_16166276","title":"Marrying immunotherapy with chemotherapy: why say IDO?","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16166276","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30940655","id":"PMC_30940655","title":"Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30940655","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20181893","id":"PMC_20181893","title":"Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20181893","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17430117","id":"PMC_17430117","title":"Chronic immune activation underlies morbid obesity: is IDO a key player?","date":"2007","source":"Current drug metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17430117","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17876564","id":"PMC_17876564","title":"IDO-expressing regulatory dendritic cells in cancer and chronic infection.","date":"2007","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/17876564","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26110930","id":"PMC_26110930","title":"Indoleamine 2,3 Dioxygenase (IDO) Expression and Activity in Relapsing-Remitting Multiple Sclerosis.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26110930","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25519303","id":"PMC_25519303","title":"The role of IDO in brain tumor immunotherapy.","date":"2014","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25519303","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17700060","id":"PMC_17700060","title":"Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer.","date":"2007","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17700060","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31525930","id":"PMC_31525930","title":"Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1).","date":"2019","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31525930","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37196768","id":"PMC_37196768","title":"IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37196768","citation_count":68,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28673995","id":"PMC_28673995","title":"Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28673995","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33708223","id":"PMC_33708223","title":"Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33708223","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17393386","id":"PMC_17393386","title":"On watching the watchers: IDO and type I/II IFN.","date":"2007","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17393386","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27470005","id":"PMC_27470005","title":"IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity.","date":"2016","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/27470005","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25368620","id":"PMC_25368620","title":"Immunological Relevance of the Coevolution of IDO1 and AHR.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25368620","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20228228","id":"PMC_20228228","title":"Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway.","date":"2010","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20228228","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21517752","id":"PMC_21517752","title":"The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer.","date":"2011","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21517752","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25787773","id":"PMC_25787773","title":"A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer.","date":"2015","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/25787773","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25756191","id":"PMC_25756191","title":"Interferon Lambda Upregulates IDO1 Expression in Respiratory Epithelial Cells After Influenza Virus Infection.","date":"2015","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/25756191","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21543643","id":"PMC_21543643","title":"Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21543643","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16365430","id":"PMC_16365430","title":"Nitration and inactivation of IDO by peroxynitrite.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16365430","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29980987","id":"PMC_29980987","title":"Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy.","date":"2018","source":"BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29980987","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37200049","id":"PMC_37200049","title":"Paraptosis Inducer to Effectively Trigger Immunogenic Cell Death for Metastatic Tumor Immunotherapy with IDO Inhibition.","date":"2023","source":"ACS nano","url":"https://pubmed.ncbi.nlm.nih.gov/37200049","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29372535","id":"PMC_29372535","title":"PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma.","date":"2018","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29372535","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34572979","id":"PMC_34572979","title":"Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/34572979","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22519427","id":"PMC_22519427","title":"The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy.","date":"2012","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/22519427","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37196407","id":"PMC_37196407","title":"Self-driven nanoprodrug platform with enhanced ferroptosis for synergistic photothermal-IDO immunotherapy.","date":"2023","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/37196407","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28336214","id":"PMC_28336214","title":"Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor.","date":"2017","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28336214","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25215657","id":"PMC_25215657","title":"Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes.","date":"2014","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25215657","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17430109","id":"PMC_17430109","title":"Tryptophan catabolism in IDO+ plasmacytoid dendritic cells.","date":"2007","source":"Current drug metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17430109","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17661345","id":"PMC_17661345","title":"IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4.","date":"2007","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/17661345","citation_count":49,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31884118","id":"PMC_31884118","title":"IDO activation, inflammation and musculoskeletal disease.","date":"2019","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/31884118","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38898702","id":"PMC_38898702","title":"Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy.","date":"2024","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/38898702","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21118329","id":"PMC_21118329","title":"Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin.","date":"2010","source":"European journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21118329","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30660652","id":"PMC_30660652","title":"Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30660652","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21517757","id":"PMC_21517757","title":"Regulation of expression and function of IDO in human dendritic cells.","date":"2011","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21517757","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30268986","id":"PMC_30268986","title":"IDO1 impairs NK cell cytotoxicity by decreasing NKG2D/NKG2DLs via promoting miR-18a.","date":"2018","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30268986","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27174915","id":"PMC_27174915","title":"IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27174915","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33813026","id":"PMC_33813026","title":"Tryptophan metabolism in brain tumors - IDO and beyond.","date":"2021","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33813026","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17430113","id":"PMC_17430113","title":"Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease.","date":"2007","source":"Current drug metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17430113","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25360135","id":"PMC_25360135","title":"AhR-Mediated, Non-Genomic Modulation of IDO1 Function.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25360135","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16411715","id":"PMC_16411715","title":"DFT-INDO/S modeling of new high molar extinction coefficient charge-transfer sensitizers for solar cell applications.","date":"2006","source":"Inorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16411715","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30773421","id":"PMC_30773421","title":"4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors.","date":"2019","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30773421","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35493480","id":"PMC_35493480","title":"Impact of IDO1 and IDO2 on the B Cell Immune Response.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35493480","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35696861","id":"PMC_35696861","title":"Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35696861","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28264972","id":"PMC_28264972","title":"Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism.","date":"2017","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/28264972","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34407414","id":"PMC_34407414","title":"Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34407414","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36706593","id":"PMC_36706593","title":"Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4+CD25+Foxp3+Tregs through IDO-Kyn-AHR axis.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36706593","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33159421","id":"PMC_33159421","title":"Class IA PI3Ks regulate subcellular and functional dynamics of IDO1.","date":"2020","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/33159421","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33021155","id":"PMC_33021155","title":"FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors.","date":"2020","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33021155","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36781714","id":"PMC_36781714","title":"PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1.","date":"2023","source":"Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36781714","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24795458","id":"PMC_24795458","title":"S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/24795458","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26579709","id":"PMC_26579709","title":"IDO Downregulation Induces Sensitivity to Pemetrexed, Gemcitabine, FK866, and Methoxyamine in Human Cancer Cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26579709","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30103191","id":"PMC_30103191","title":"Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors.","date":"2018","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30103191","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36776388","id":"PMC_36776388","title":"DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36776388","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35990703","id":"PMC_35990703","title":"Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.","date":"2022","source":"Neuro-oncology advances","url":"https://pubmed.ncbi.nlm.nih.gov/35990703","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36812891","id":"PMC_36812891","title":"An adverse tumor-protective effect of IDO1 inhibition.","date":"2023","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36812891","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31033497","id":"PMC_31033497","title":"Expression of Indoleamine 2, 3-dioxygenase 1 (IDO1) and Tryptophanyl-tRNA Synthetase (WARS) in Gastric Cancer Molecular Subtypes.","date":"2020","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/31033497","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31511064","id":"PMC_31511064","title":"Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy.","date":"2019","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31511064","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32055299","id":"PMC_32055299","title":"Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.","date":"2019","source":"MedChemComm","url":"https://pubmed.ncbi.nlm.nih.gov/32055299","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34907770","id":"PMC_34907770","title":"Structure and Plasticity of Indoleamine 2,3-Dioxygenase 1 (IDO1).","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34907770","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32194552","id":"PMC_32194552","title":"IDO Targeting in Sarcoma: Biological and Clinical Implications.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32194552","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30381008","id":"PMC_30381008","title":"FoxP3 and IDO in Canine Melanocytic Tumors.","date":"2018","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/30381008","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31753057","id":"PMC_31753057","title":"Effects of IDO1 and TDO2 inhibition on cognitive deficits and anxiety following LPS-induced neuroinflammation.","date":"2019","source":"Acta neuropsychiatrica","url":"https://pubmed.ncbi.nlm.nih.gov/31753057","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37122718","id":"PMC_37122718","title":"The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37122718","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36733497","id":"PMC_36733497","title":"The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma.","date":"2023","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/36733497","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39061097","id":"PMC_39061097","title":"Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39061097","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9712583","id":"PMC_9712583","title":"Prevention of allogeneic fetal rejection by tryptophan catabolism.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9712583","citation_count":2022,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14502282","id":"PMC_14502282","title":"Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14502282","citation_count":1847,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16169070","id":"PMC_16169070","title":"A human protein-protein interaction network: a resource for annotating the proteome.","date":"2005","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16169070","citation_count":1704,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23986400","id":"PMC_23986400","title":"Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.","date":"2013","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23986400","citation_count":1445,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15001472","id":"PMC_15001472","title":"Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15001472","citation_count":1300,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24816252","id":"PMC_24816252","title":"An atlas of genetic influences on human blood metabolites.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24816252","citation_count":1209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15711557","id":"PMC_15711557","title":"Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.","date":"2005","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15711557","citation_count":889,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17951526","id":"PMC_17951526","title":"Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17951526","citation_count":871,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12228717","id":"PMC_12228717","title":"Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase.","date":"2002","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12228717","citation_count":807,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12186837","id":"PMC_12186837","title":"Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites.","date":"2002","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12186837","citation_count":767,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15254595","id":"PMC_15254595","title":"Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes.","date":"2004","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/15254595","citation_count":720,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12738417","id":"PMC_12738417","title":"Tolerance, DCs and tryptophan: much ado about IDO.","date":"2003","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12738417","citation_count":605,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23752227","id":"PMC_23752227","title":"Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4.","date":"2013","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23752227","citation_count":538,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16489067","id":"PMC_16489067","title":"Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16489067","citation_count":523,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23440412","id":"PMC_23440412","title":"Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23440412","citation_count":495,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20484731","id":"PMC_20484731","title":"Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease.","date":"2010","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20484731","citation_count":443,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22932670","id":"PMC_22932670","title":"IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival.","date":"2012","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/22932670","citation_count":384,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18832696","id":"PMC_18832696","title":"The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18832696","citation_count":380,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16477023","id":"PMC_16477023","title":"Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase.","date":"2006","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/16477023","citation_count":346,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15947091","id":"PMC_15947091","title":"A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15947091","citation_count":315,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22751107","id":"PMC_22751107","title":"Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression.","date":"2012","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22751107","citation_count":276,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16176799","id":"PMC_16176799","title":"Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16176799","citation_count":261,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19353519","id":"PMC_19353519","title":"Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R.","date":"2009","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/19353519","citation_count":261,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28053021","id":"PMC_28053021","title":"First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.","date":"2017","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/28053021","citation_count":252,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17158233","id":"PMC_17158233","title":"HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17158233","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46939,"output_tokens":7075,"usd":0.123471},"stage2":{"model":"claude-opus-4-6","input_tokens":10806,"output_tokens":2941,"usd":0.191332},"total_usd":0.691231,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60097,"output_tokens":7073,"usd":0.143193},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":11098,"output_tokens":4000,"usd":0.233235}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"IDO (indoleamine 2,3-dioxygenase) is an enzyme expressed by dendritic cells that degrades the essential amino acid tryptophan, and cells expressing IDO can suppress T-cell responses and promote tolerance through tryptophan catabolism.\",\n      \"method\": \"Review synthesizing experimental evidence from mammalian pregnancy, tumor resistance, chronic infections, and autoimmune disease models\",\n      \"journal\": \"Nature reviews. Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent labs, broad experimental validation across multiple biological contexts\",\n      \"pmids\": [\"15459668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IDO1 is nitrated and inactivated by peroxynitrite; mass spectrometry and mutagenesis identified Tyr15, Tyr345, and Tyr353 as nitration sites, with Tyr15 being the most critical residue for enzyme inactivation.\",\n      \"method\": \"In vitro enzyme activity assay with peroxynitrite generator, immunoprecipitation of IDO from cells, recombinant IDO treatment, Tyr-to-Phe mutagenesis, LC/ESI-MS/MS peptide analysis, nitrotyrosine immunodetection\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with recombinant protein, site-directed mutagenesis confirming Tyr15 as critical residue, orthogonal methods\",\n      \"pmids\": [\"16365430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IDO1 expression in microglia is induced by IFN-γ, and this induction is modulated via the PI3K pathway; inhibition of PI3K eliminates IFN-γ induction of IDO1 (but not of tryptophanyl-tRNA synthetase). IL-4 and IL-13 enhance IFN-γ-induced IDO expression through a mechanism dependent on protein phosphatase 2A (PP2A) activity.\",\n      \"method\": \"Pharmacological inhibition of PI3K and PP2A in primary microglia, cytokine stimulation, mRNA quantification\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean pharmacological dissection with multiple pathway inhibitors in primary cells, single lab\",\n      \"pmids\": [\"17661345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IDO production by plasmacytoid dendritic cells (pDCs) and by gingival fibroblasts mediates T-cell suppression through tryptophan depletion; T-cell inhibition was reversed by addition of 1-methyl-tryptophan or L-tryptophan.\",\n      \"method\": \"Mixed lymphocyte reactions with IDO-expressing cells, IDO inhibitor rescue (1-MT and L-tryptophan), TLR ligand stimulation of HGFs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue with IDO inhibitor and substrate, but single lab\",\n      \"pmids\": [\"17202379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IDO paradoxically drives B cell-mediated autoimmunity in the K/BxN rheumatoid arthritis model; IDO inhibition with 1-methyl-tryptophan reduced autoantibody titers, inflammatory cytokines, and disease severity, revealing an IDO role in stimulating autoreactive B cell responses.\",\n      \"method\": \"In vivo IDO inhibitor treatment (1-MT) in murine RA model (K/BxN), autoantibody titer measurement, cytokine analysis, disease course monitoring\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO/inhibitor experiment with defined cellular and molecular readouts, single lab\",\n      \"pmids\": [\"19494274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IDO1 induction in the gut via TLR-9 agonist (immunostimulatory DNA) requires IFN-dependent STAT-1 signaling; IDO1 (not IDO2) is induced in intestinal epithelial cells and CD11c+/CD11b+ lamina propria cells, and this IDO1 induction is critical for limiting colitis severity.\",\n      \"method\": \"TLR-9 agonist treatment of mice with experimental colitis, STAT-1 knockout mice, IDO inhibitor treatment, histological scoring, cell-type specific IDO1 expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic (STAT1 KO) and pharmacological dissection with specific IDO1 vs IDO2 identification, defined cellular context\",\n      \"pmids\": [\"20181893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IDO1 functions as a signaling molecule (independent of enzymatic activity) in plasmacytoid dendritic cells (pDCs): when phosphorylated at immunoreceptor tyrosine-based inhibitory motifs (ITIMs), IDO1 acts as a docking platform activating a non-canonical NF-κB pathway downstream of TGF-β, inducing long-lasting IDO1 expression and autocrine TGF-β production. This signaling function was defective in NOD pDCs and could be restored by IDO1 transfection.\",\n      \"method\": \"Forced IDO1 expression (transfection) in NOD pDCs, non-canonical NF-κB pathway analysis, autocrine TGF-β measurement, in vivo suppression assay, pro-inflammatory cytokine measurement\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution by forced expression with pathway-level readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"25215657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The aryl hydrocarbon receptor (AhR) contributes to IDO1 regulation through both genomic (transcriptional activation of IDO1) and potentially non-genomic mechanisms; AhR, as part of a ubiquitin ligase complex, may affect IDO1 half-life via the ubiquitin-proteasome system.\",\n      \"method\": \"Review/mechanistic analysis; pharmacological inhibition of IDO enzymatic activity with AhR agonist kynurenine, IDO1 protein stability analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — mechanistic hypothesis with partial experimental support, single lab review\",\n      \"pmids\": [\"25360135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tumor cell IDO expression recruits and activates myeloid-derived suppressor cells (MDSCs) through a mechanism dependent on regulatory T cells (Tregs), establishing an IDO-Treg-MDSC immunosuppressive axis in the tumor microenvironment.\",\n      \"method\": \"IDO-expressing tumor cell implantation in syngeneic mice, selective IDO inhibitor treatment in vivo, flow cytometry of tumor-infiltrating MDSCs and Tregs, functional suppression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo pharmacological intervention with defined cellular mechanism, single lab\",\n      \"pmids\": [\"26411680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Long-term maintenance of IDO expression in tolerogenic dendritic cells requires IDO enzymatic activity producing kynurenine and IFN-γ-induced AhR expression; kynurenine activates AhR, which then sustains IDO transcription in a positive autocrine feedback loop (IDO-kynurenine/AhR-IDO loop).\",\n      \"method\": \"In vitro DC stimulation with IFN-γ and CD40L, pharmacological IDO inhibition, exogenous kynurenine addition, AhR-deficient DC experiments, in vivo tumor-draining lymph node analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (AhR KO DCs) and pharmacological dissection, multiple orthogonal approaches confirming the feedback loop\",\n      \"pmids\": [\"27316681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IDO expression by lymph node plasmacytoid dendritic cells (pDCs) is required for conferring suppressive function to Tregs; Treg-pDC MHCII-dependent interactions drive IDO expression in pDCs, which in turn enables Treg suppressive function during autoimmunity (EAE model).\",\n      \"method\": \"Flow cytometry of LN cells, IDO-deficient pDC analysis, EAE induction, Treg suppressive function assays, antigen-specific T cell priming assays\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function (IDO-deficient pDCs) with defined cellular mechanism in vivo, single lab\",\n      \"pmids\": [\"27470005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IDO1 expression in lung parenchyma is induced in an IFN-γ-dependent manner after allogeneic hematopoietic stem cell transplantation; the IDO product kynurenine suppresses inflammatory activities of lung epithelial cells and CD4+ T cells through the aryl hydrocarbon receptor (AhR) pathway, protecting against acute lethal pulmonary inflammation (idiopathic pneumonia syndrome).\",\n      \"method\": \"IDO gene deletion, IFN-γ gene deletion in donor T cells, FK506 treatment, HDAC inhibitor treatment, kynurenine measurement, AhR pathway analysis, in vivo lethal pulmonary inflammation model\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockouts converge on same mechanism, in vivo model with defined molecular pathway\",\n      \"pmids\": [\"28673995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IDO1 inhibition with regorafenib (via RET-Src axis targeting) attenuates JAK1/2-STAT1 and MAPK signaling, thereby suppressing IFN-γ-induced IDO1 expression in melanoma cells without affecting MHC-I expression.\",\n      \"method\": \"Kinase inhibitor library screening, flow cytometry of PD-L1 levels, in vitro/in vivo combination studies, RET/Src pathway analysis, mouse syngeneic tumor models\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and pathway dissection with in vitro/in vivo correlation, single lab\",\n      \"pmids\": [\"30940655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IDO1 impairs NK cell cytotoxicity by promoting miR-18a expression; miR-18a targets the 3'UTR of NKG2D and NKG2D ligand (Mult-1), and IDO1 promotes miR-18a/AGO2 complex formation leading to Mult-1 mRNA degradation and translational inhibition of NKG2D.\",\n      \"method\": \"Co-culture of tumor cell supernatant with NK cells, qPCR, miRNA binding site prediction and validation, AGO2 co-immunoprecipitation, IDO1 inhibitor (INCB024360) rescue, 3'UTR reporter assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — AGO2 Co-IP, inhibitor rescue, and 3'UTR target validation, though single lab\",\n      \"pmids\": [\"30268986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDO1 and COL12A1 synergistically promote gastric cancer metastasis; IDO1 metabolite kynurenine drives a positive feedback loop with COL12A1 via integrin β1 and MAPK signaling pathway to promote cell migration.\",\n      \"method\": \"IDO1 knockdown in GC cell lines, WGCNA analysis of GC transcriptomic data, Western blot, qPCR, migration assays, popliteal lymph node metastasis in vivo model, exogenous kynurenine treatment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IDO1 KD with defined molecular pathway in vitro and in vivo, single lab\",\n      \"pmids\": [\"31315643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IDO1 translocates from the cytosol to early endosomes under conditions favoring signaling over catalytic activity; this spatial shift requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated and are required for full expression of IDO1-dependent immunoregulatory phenotype in plasmacytoid dendritic cells.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging, Co-IP with PI3K subunits, PI3K inhibitor treatment, IDO1 signaling readouts in pDCs, in vivo immunoregulatory phenotype assessment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (fractionation, imaging, Co-IP, genetic/pharmacological PI3K perturbation, in vivo validation) in single study\",\n      \"pmids\": [\"33159421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IDO1 and TDO promote glioma cell motility through the Kyn-AhR-AQP4 signaling pathway; IDO1/TDO-derived kynurenine activates AhR which upregulates aquaporin 4 (AQP4) to enhance cell migration.\",\n      \"method\": \"Clinical sample analysis, IDO1/TDO inhibitor treatment, in vitro migration assays in U87MG cells, AhR pathway analysis, orthotopic glioma mouse model with IDO1/TDO dual inhibitor\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined pathway with pharmacological inhibition in vitro and in vivo, single lab\",\n      \"pmids\": [\"32296044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tumor cell IDO1 increases complement factor H (CFH) and factor H-like protein 1 (FHL-1) expression independent of tryptophan metabolism (non-enzymic function); IDO enzyme-null mutant reconstituted in GBM cells still increased CFH/FHL-1 and increased intratumoral Tregs and MDSCs while decreasing survival in mice.\",\n      \"method\": \"IDO1-deficient GBM cell lines reconstituted with wild-type or enzyme-null IDO1 cDNA, microarray analysis, ex vivo coculture, syngeneic and humanized mouse GBM models, TCGA analysis, human patient plasma and tumor analysis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with enzyme-null mutant separating catalytic from non-catalytic function, multiple orthogonal in vitro and in vivo models\",\n      \"pmids\": [\"34479957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP14, a proteasome-associated deubiquitinating enzyme, stabilizes IDO1 protein post-translationally; USP14 overexpression promotes tryptophan metabolism and T-cell dysfunction, while USP14 knockdown decreases IDO1 expression and reverses T-cell suppression.\",\n      \"method\": \"USP14 overexpression and knockdown experiments, immunoprecipitation, ubiquitination assays, USP14 inhibitor treatment, MC38 syngeneic mouse model with anti-PD-1 combination\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP/ubiquitination assay establishing deubiquitinase-substrate relationship, in vitro and in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"36163134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IDO1 contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, when phosphorylated, trigger suppressive signaling through binding of PI3K p110 and SHP-1 proteins independently of IDO1 catalytic activity.\",\n      \"method\": \"Review synthesizing ITIM phosphorylation data, molecular interaction studies with PI3K p110 and SHP-1\",\n      \"journal\": \"Ageing research reviews\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — review citing prior experimental work; original binding experiments described elsewhere\",\n      \"pmids\": [\"35085834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDO1 inhibitors such as 1,2,3-triazole MMG-0358 inhibit IDO1 through distinct molecular mechanisms; X-ray crystallography revealed the binding mode of MMG-0358 to IDO1, enabling classification of inhibitors by inhibition mechanism (competitive, uncompetitive, suicide inhibitors, etc.).\",\n      \"method\": \"X-ray crystallography, enzyme kinetics, multiple inhibitor characterization, computational docking\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional kinetic validation, first structure of triazole inhibitor complex\",\n      \"pmids\": [\"31525930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IDO1 has conformational plasticity and, in addition to catalytic activity, performs a non-enzymic signaling function that reprograms expression profiles of immune cells toward an immunoregulatory phenotype.\",\n      \"method\": \"Review synthesizing structural biology, enzymatic, and signaling function studies of IDO1\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — review synthesizing multiple experimental findings from multiple labs including structural and signaling data\",\n      \"pmids\": [\"34145969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IDO1-mediated kynurenine production is required for hypoxic preconditioning-induced renoprotection; IDO1 deficiency abolishes systemic kynurenine increase and renoprotection from ischemic kidney injury, and exogenous kynurenine restores protection in IDO1-deficient animals, with the mechanism involving NAD+ preservation.\",\n      \"method\": \"Serum metabolomic profiling, IDO1-knockout mice, pharmacologic PHD inhibition, exogenous kynurenine administration, ischemia-reperfusion kidney injury model, NAD+ measurement\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with metabolomic profiling and functional rescue by substrate administration, multiple orthogonal approaches\",\n      \"pmids\": [\"34407414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The non-enzymic signaling function of IDO1 in tumor cells (B16-F10 melanoma) accelerates tumor growth via increased Ras and Erk activities; cells expressing enzyme-null but signaling-competent IDO1 (H350A mutant) showed faster growth than wild-type IDO1-expressing cells and increased Foxp3+ Tregs and decreased CD8+ T cells in vivo.\",\n      \"method\": \"B16-F10 cells transfected with wild-type or H350A catalytic mutant IDO1, in vitro growth assays, Ras/Erk activity measurement, syngeneic mouse tumor models, flow cytometry of tumor-infiltrating immune cells\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzyme-null mutant reconstitution separating catalytic from signaling function, in vitro and in vivo validation with defined molecular readouts\",\n      \"pmids\": [\"36733497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The catalytic IDO1 inhibitor epacadostat can paradoxically enhance the non-enzymatic signaling function of IDO1, potentially explaining its clinical failure; epacadostat blocks enzymatic tryptophan catabolism while potentiating the immunoregulatory signaling function of IDO1.\",\n      \"method\": \"Cell-based assays for IDO1 enzymatic activity and signaling function, epacadostat treatment of pDCs, IDO1 phosphorylation and downstream signaling readouts\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection separating enzymatic vs signaling activity with pharmacological tool, single lab\",\n      \"pmids\": [\"37122718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IDO1 inhibition by IFN-γ-mediated tryptophan depletion leads to amino acid deprivation-dependent stress response activating ATF4 and suppressing MITF in melanoma cells; IDO1 inhibition with epacadostat reverses IFN-γ-induced suppression of general protein translation in melanoma cells and restores MITF expression, conferring resistance to T cell killing.\",\n      \"method\": \"RNA sequencing, ribosome profiling, IDO1 inhibitor treatment, ATF4/MITF expression analysis, single-cell sequencing of patient melanomas, MITF reconstitution experiments, T cell killing assays\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ribosome profiling, transcriptomics, genetic reconstitution, and functional T cell killing assays in single study\",\n      \"pmids\": [\"36812891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Artesunate directly targets IDO1 to suppress Hic1-mediated transcriptional repression of Hmox1, resulting in melanoma cell ferroptosis; simultaneously, IDO1 targeting elevates tryptophan levels in CD8+ T cells, inhibiting NFATc1-mediated PD1 transcription and activating CD8+ T cells.\",\n      \"method\": \"Direct binding assay of artesunate to IDO1, Hic1/Hmox1 pathway analysis, ferroptosis assays, PD1 transcription analysis, in vivo mouse melanoma model, CD8+ T cell functional assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct target binding with downstream pathway validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"39061097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IDO1 involvement in mTOR signaling: inhibition of mTOR strongly induces IDO1 expression and activity in medulloblastoma cells, with IDO1 counteracting rapamycin treatment by recruiting Treg cells; the mTOR/IDO1 crosstalk is specific to medulloblastoma cells.\",\n      \"method\": \"Analysis of MB tissue specimens for mTOR and IDO1 expression, in vitro mTOR inhibition with rapamycin, IDO1 expression/activity measurement, Treg recruitment assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological mTOR inhibition with defined IDO1 induction readout, correlation in patient specimens and cell lines, single lab\",\n      \"pmids\": [\"27174915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-32γ from multiple myeloma cells promotes IDO expression in macrophages through the PR3 (proteinase 3) receptor and subsequent STAT3 and NF-κB pathway activation; IDO-positive macrophages educated by IL-32γ inhibit CD4+ T cell proliferation and cytokine production.\",\n      \"method\": \"RNA-sequencing, qRT-PCR, Western blot, PR3 knockdown, STAT3/NF-κB pathway inhibitors, IL-32 knockdown in MM cells, IDO1 immunofluorescence, T cell co-culture assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown of both ligand and receptor with defined pathway inhibition, multiple methods, single lab\",\n      \"pmids\": [\"30660652\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDO1 is a heme-containing cytosolic enzyme that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine (first step of the kynurenine pathway), suppressing immunity via tryptophan depletion (activating GCN2) and kynurenine accumulation (activating AhR to generate tolerogenic DCs and Tregs); beyond its catalytic activity, IDO1 functions as a signaling molecule in plasmacytoid DCs through phosphorylatable ITIM motifs that recruit PI3K p110/SHP-1 and activate non-canonical NF-κB downstream of TGF-β, a non-enzymic signaling function that is spatially regulated by IDO1 translocation from cytosol to early endosomes in a class IA PI3K-dependent manner, and this same non-enzymic function occurs in tumor cells to drive Ras/Erk-mediated malignant progression; IDO1 protein stability is post-translationally controlled by the deubiquitinase USP14, and its enzymatic activity is subject to inactivation by peroxynitrite-mediated tyrosine nitration (primarily at Tyr15).\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"IDO-mediated tryptophan catabolism by trophoblasts and macrophages at the maternal-fetal interface is required to suppress maternal T-cell responses and prevent allogeneic fetal rejection; pharmacological inhibition of IDO with 1-methyltryptophan caused rapid rejection of allogeneic concepti in pregnant mice.\",\n      \"method\": \"Pharmacological inhibition in vivo (1-methyl-tryptophan treatment of pregnant mice) with fetal survival readout\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo genetic/pharmacological experiment with defined phenotypic readout; foundational paper with >2000 citations replicated widely\",\n      \"pmids\": [\"9712583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A subset of human plasmacytoid dendritic cells (pDCs) constitutively expresses IDO and suppresses T-cell proliferation in vitro; IDO-positive APCs were identified by co-expression of CD123 and CCR6 surface markers.\",\n      \"method\": \"Flow cytometry cell-surface phenotyping, in vitro T-cell suppression assay with IDO-expressing DC subset\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional IDO activity linked to defined DC subset, replicated by multiple subsequent labs\",\n      \"pmids\": [\"12228717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IDO-expressing dendritic cells suppress allogeneic T-cell proliferation by depleting tryptophan and producing kynurenine pathway metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid), which are directly cytotoxic to activated T, B, and NK cells but not DCs.\",\n      \"method\": \"Adenoviral IDO gene transduction of human DCs, in vitro mixed lymphocyte reactions, metabolite supplementation/rescue assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted IDO activity in DCs with metabolite-level mechanistic dissection and rescue experiments\",\n      \"pmids\": [\"12186837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Most human tumors constitutively express IDO, and IDO expression by immunogenic mouse tumor cells prevents T-cell accumulation at the tumor site and immune rejection; systemic IDO inhibition partially reverses this immune escape.\",\n      \"method\": \"IDO expression screening in human tumor samples; IDO transfection into mouse tumor cells; in vivo T-cell accumulation and tumor rejection assays with IDO inhibitor treatment\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function (IDO transfection) combined with pharmacological inhibition in vivo; foundational cancer-immunology discovery paper\",\n      \"pmids\": [\"14502282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse tumor-draining lymph nodes contain a subset of pDCs that constitutively express immunosuppressive levels of IDO; these pDCs potently suppress T-cell responses and adoptive transfer creates antigen-specific T-cell anergy prevented by IDO gene disruption or IDO inhibitor treatment.\",\n      \"method\": \"Flow cytometry, adoptive transfer, IDO knockout mice, in vitro suppression assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (IDO KO) and pharmacological evidence combined with adoptive transfer functional readout\",\n      \"pmids\": [\"15254595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human bone marrow stromal cells (MSCs) express IDO upon IFN-γ stimulation and inhibit allogeneic T-cell responses through IDO-mediated tryptophan degradation; addition of excess tryptophan restores T-cell proliferation.\",\n      \"method\": \"IFN-γ stimulation of MSCs, IDO activity measurement (kynurenine production), mixed lymphocyte reactions with tryptophan rescue\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional IDO activity assay combined with substrate rescue experiment\",\n      \"pmids\": [\"15001472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IDO expression is under genetic control of Bin1; Bin1 loss elevates IDO expression through STAT1- and NF-κB-dependent pathways, facilitating immune escape of oncogenically transformed cells; small-molecule IDO inhibitors cooperate with cytotoxic chemotherapy to cause regression of established tumors in MMTV-Neu breast cancer mice.\",\n      \"method\": \"Bin1 knockout mouse studies, STAT1/NF-κB pathway analysis, in vivo tumor regression with IDO inhibitor + chemotherapy combination\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (Bin1 KO) combined with defined downstream transcription factor pathway and in vivo pharmacological validation\",\n      \"pmids\": [\"15711557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Prostaglandin E2 (PGE2) induces IDO mRNA expression in monocyte-derived DCs via the Gs-protein-coupled EP2 receptor and adenylate cyclase activation, but a second signal through TNF receptor or a TLR is required to activate IDO enzyme activity.\",\n      \"method\": \"Quantitative IDO mRNA, protein, and enzyme activity assays; pharmacological receptor antagonism; two-step stimulation dissection\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal assays (mRNA, protein, enzymatic activity) with receptor-specific pharmacological dissection\",\n      \"pmids\": [\"15947091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of human IDO at 2.3 Å resolution reveals two α-helical domains flanking a heme group; mutagenesis shows no polar residue in the distal heme pocket is essential for activity, supporting a reaction mechanism where iron-bound dioxygen abstracts a proton from L-tryptophan; residues F226, F227, and R231 maintain shape complementarity for substrate positioning.\",\n      \"method\": \"X-ray crystallography of IDO-4-phenylimidazole/cyanide complex; active-site mutagenesis; substrate-binding affinity assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and catalytic mechanism validation\",\n      \"pmids\": [\"16477023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IDO is nitrated and enzymatically inactivated by peroxynitrite; liquid chromatography/tandem MS identified Tyr15, Tyr345, and Tyr353 as nitration sites in recombinant IDO; Tyr15-to-Phe mutation significantly reduces nitration-dependent inactivation, establishing Tyr15 as the critical residue.\",\n      \"method\": \"Peroxynitrite treatment of immunoprecipitated and recombinant IDO, nitrotyrosine detection by immunoprecipitation and LC/ESI-MS/MS, Tyr15Phe mutagenesis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzyme inactivation with mass-spectrometric site identification and site-directed mutagenesis validation\",\n      \"pmids\": [\"16365430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"MSCs inhibit IL-2-induced NK-cell proliferation, cytotoxic activity, cytokine production, and down-regulation of activating NK receptors (NKp30, NKp44, NKG2D) through IDO and prostaglandin E2 as key mediators.\",\n      \"method\": \"MSC/NK cell co-culture, IDO inhibitor (1-methyl-tryptophan) and COX inhibitor treatment, flow cytometry of NK receptor expression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibitor dissection with multiple functional readouts (proliferation, cytotoxicity, receptor expression)\",\n      \"pmids\": [\"17951526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IDO expression in plasmacytoid dendritic cells is induced by IFN-γ and is required for pDC-driven generation of inducible FoxP3+ regulatory T cells from CD4+CD25- T cells; kynurenine (the immediate IDO metabolite) bypasses IDO inhibition and restores Treg generation, implicating kynurenine production as the critical downstream mediator.\",\n      \"method\": \"TLR9 stimulation of human pDCs, IDO inhibitor (1-methyl-D-tryptophan) blocking, kynurenine supplementation rescue, Treg suppressor function assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition combined with metabolite rescue in a defined cellular system\",\n      \"pmids\": [\"18832696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TLR ligation on human bone marrow-derived MSCs enhances IDO1-dependent immunosuppression through an autocrine IFN-β signaling loop dependent on protein kinase R (PKR), but independent of IFN-γ.\",\n      \"method\": \"TLR ligand stimulation of MSCs, IFN-β neutralization, PKR pharmacological inhibition, IDO1 activity measurement (kynurenine production)\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of PKR/IFN-β/IDO1 axis with multiple inhibitor approaches\",\n      \"pmids\": [\"19353519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Progressive HIV disease induces IDO1 in myeloid antigen-presenting DCs, and IDO1-derived 3-hydroxyanthranilic acid directly mediates loss of Th17 cells and reciprocal increase of Treg cells; this imbalance correlates with microbial translocation and sustained inflammation.\",\n      \"method\": \"HIV patient samples (blood and biopsies), in vitro IDO inhibitor experiments, addition of specific tryptophan catabolites to T-cell cultures with Th17/Treg readout\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — specific catabolite (3-hydroxyanthranilic acid) identified as direct mediator via in vitro reconstitution, corroborated by clinical samples\",\n      \"pmids\": [\"20484731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Brain IDO1 upregulation in hippocampus mediates comorbidity of pain and depression; chronic pain induces IDO1 expression via IL-6/JAK/STAT pathway, increasing the kynurenine/tryptophan ratio and decreasing serotonin/tryptophan ratio; IDO1 knockout or pharmacological inhibition attenuates both nociceptive and depressive behavior.\",\n      \"method\": \"Rat chronic pain model, intra-hippocampal IL-6 injection, IDO1 KO mice, pharmacological IDO1 inhibition, HPLC metabolite measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (KO) and pharmacological approaches with defined molecular pathway (IL-6/JAK/STAT → IDO1) and multiple behavioral/biochemical readouts\",\n      \"pmids\": [\"22751107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDO expression in the tumor microenvironment is driven by CD8+ T cells via IFN-γ signaling; PD-L1 and Treg recruitment also depend on intratumoral CD8+ T cells, revealing IDO as a T-cell-induced negative feedback mechanism rather than a pre-existing tumor escape program.\",\n      \"method\": \"Murine tumor models with T-cell depletion and IFN-γ neutralization; correlation of CD8+ T-cell presence with IDO expression in human tumors\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic depletion experiments in vivo establishing upstream regulatory dependence on CD8+ T cells and IFN-γ\",\n      \"pmids\": [\"23986400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IDO is a critical resistance mechanism to anti-CTLA-4 immunotherapy; IDO knockout mice show striking tumor growth delay and improved survival with anti-CTLA-4 treatment; IDO inhibitors synergize with anti-CTLA-4, anti-PD-1, and anti-GITR antibodies by enhancing effector T-cell infiltration and increasing effector-to-Treg ratios in tumors.\",\n      \"method\": \"IDO knockout mouse tumor models, IDO inhibitor + immune checkpoint antibody combination experiments, flow cytometry of tumor-infiltrating immune cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (IDO KO) combined with pharmacological approach with multiple immunological readouts\",\n      \"pmids\": [\"23752227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IDO1 contains immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that, upon phosphorylation, act as docking sites for signaling partners including SHP-1 phosphatase and PI3K p110; this non-enzymatic signaling function activates the non-canonical NF-κB pathway in pDCs and induces long-lasting autocrine TGF-β production and immunosuppressive phenotype, independent of tryptophan catabolism.\",\n      \"method\": \"Transfection of NOD pDCs with IDO1 constructs, NF-κB pathway analysis, TGF-β measurement, cytokine production assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution of IDO1 signaling function in deficient cells with defined pathway (ITIM phosphorylation → SHP-1/PI3K → non-canonical NF-κB → TGF-β) and multiple readouts\",\n      \"pmids\": [\"25215657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IDO expressed by tumor cells recruits and activates myeloid-derived suppressor cells (MDSCs) through a mechanism dependent on regulatory T cells (Tregs); IDO inhibition in vivo reverses immunosuppression by decreasing tumor-infiltrating MDSCs and Tregs and abolishing their suppressive function.\",\n      \"method\": \"Syngeneic tumor models with IDO-expressing tumor cells, IDO inhibitor treatment in vivo, flow cytometry of MDSC/Treg populations, functional suppression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of IDO-Treg-MDSC axis with pharmacological intervention and multiple cellular readouts\",\n      \"pmids\": [\"26411680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IFN-γ-induced IDO expression in DCs initiates an autocrine IDO-kynurenine/AhR-IDO positive feedback loop that maintains long-term IDO expression independent of exogenous IFN-γ; both IDO enzymatic activity and AhR expression are required for sustained IDO transcription, and kynurenine added to IDO-inhibited DC cultures restores IDO expression only in AhR-expressing DCs.\",\n      \"method\": \"In vitro DC stimulation with IFN-γ/CD40L, IDO inhibitor treatment, kynurenine supplementation rescue, AhR-deficient DC comparison, in vivo validation in tumor-bearing mice\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of autocrine feedback loop using pharmacological blockade and AhR-deficient cells with both in vitro and in vivo validation\",\n      \"pmids\": [\"27316681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IDO expression in lung parenchyma is induced by IFN-γ from donor CD4+ T cells early after allogeneic hematopoietic stem cell transplantation; loss of IDO (gene deletion or IFN-γ blockade) results in acute lethal pulmonary inflammation (idiopathic pneumonia syndrome); IL-6 can induce IDO in an IFN-γ-independent manner when STAT3 deacetylation is inhibited; IDO-derived kynurenine suppresses inflammatory activity of lung epithelial cells and CD4+ T cells through the AhR pathway.\",\n      \"method\": \"IDO gene knockout mice, IFN-γ gene knockout donor T cells, HDAC inhibitor treatment, FK506 immunosuppression model, in vitro IL-6/STAT3/IDO pathway analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic models combined with pharmacological interventions, with defined cytokine pathways and AhR downstream signaling\",\n      \"pmids\": [\"28673995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IDO1 inhibition mechanisms were characterized for multiple inhibitor classes; X-ray structure of the 1,2,3-triazole inhibitor MMG-0358 bound to IDO1 was determined; inhibitors were classified into mechanistic categories based on their mode of binding to the active site heme iron and surrounding residues.\",\n      \"method\": \"X-ray crystallography of IDO1-inhibitor complexes, enzyme kinetics, computational modeling\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with functional kinetic validation\",\n      \"pmids\": [\"31525930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Under conditions favoring signaling rather than catabolic activity, IDO1 shifts from the cytosol to early endosomes; this subcellular translocation requires interaction with class IA phosphoinositide 3-kinases (PI3Ks), which become activated and are required for full expression of the IDO1-dependent immunoregulatory phenotype in pDCs in vivo.\",\n      \"method\": \"Live-cell imaging, subcellular fractionation, PI3K inhibitors, in vivo pDC functional assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization experiment linked to functional consequence with pharmacological PI3K inhibition and in vivo validation\",\n      \"pmids\": [\"33159421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Non-enzymatic (signaling) IDO1 activity in GBM tumor cells increases complement factor H (CFH) and its isoform FHL-1 expression independent of tryptophan metabolism; elevated CFH/FHL-1 increases tumor-infiltrating Tregs and MDSCs while decreasing CD8+ T cells and overall survival.\",\n      \"method\": \"IDO1 enzyme-null mutant reconstitution in GBM cell lines, microarray transcriptomic analysis, syngeneic and humanized mouse models, ex vivo co-culture assays\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — IDO1 catalytically-dead mutant reconstitution identifies non-enzymatic function with defined molecular target (CFH/FHL-1) validated in multiple in vivo models\",\n      \"pmids\": [\"34479957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP14, a proteasome-associated deubiquitinating enzyme, stabilizes IDO1 protein post-translationally; USP14 overexpression promotes tryptophan metabolism and T-cell dysfunction; knockdown or pharmacological inhibition of USP14 decreases IDO1 expression and reverses T-cell suppression in a syngeneic mouse model.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, USP14 knockdown/pharmacological inhibition, MC38 syngeneic mouse model with anti-PD-1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying deubiquitinase-substrate relationship combined with in vitro and in vivo functional validation\",\n      \"pmids\": [\"36163134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The non-enzymatic (signaling) function of IDO1 in B16-F10 melanoma tumor cells accelerates tumor cell proliferation through increased Ras and Erk activities, reduces CD8+ T-cell tumor infiltration, and increases FoxP3+ Treg infiltration; a catalytically-dead IDO1 mutant (H350A) that retains signaling capacity reproduces these effects both in vitro and in vivo.\",\n      \"method\": \"IDO1 wild-type and catalytic mutant (H350A) transfection into B16-F10 cells, Ras/Erk activity assays, syngeneic in vivo tumor models, flow cytometry of tumor-infiltrating lymphocytes\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — catalytically-dead mutant isolates non-enzymatic function with defined signaling pathway (Ras/Erk) and in vivo immune infiltrate readout\",\n      \"pmids\": [\"36733497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The IDO1 catalytic inhibitor epacadostat enhances the non-enzymatic (signaling/ITIM-mediated) immunosuppressive function of IDO1, providing a mechanistic explanation for its clinical failure; blocking enzymatic activity alone may be insufficient if signaling function is simultaneously potentiated.\",\n      \"method\": \"ITIM phosphorylation assays, signaling pathway analysis in IDO1-expressing immune cells treated with epacadostat, comparison of enzymatic vs. signaling IDO1 outputs\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — single laboratory study linking epacadostat to enhanced ITIM signaling, mechanistic but not yet independently replicated\",\n      \"pmids\": [\"37122718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IDO1 contains two ITIM motifs that, when phosphorylated, recruit SHP-1 and PI3K p110 to trigger immunosuppressive signaling independent of catalytic activity; this non-enzymatic function reprograms immune cell gene expression toward an immunoregulatory phenotype.\",\n      \"method\": \"ITIM mutant constructs, phosphorylation assays, SHP-1/PI3K co-immunoprecipitation, gene expression profiling\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (mutagenesis, co-IP, gene expression) establishing ITIM-mediated signaling mechanism, corroborated by multiple studies from different labs\",\n      \"pmids\": [\"34145969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The IDO1/kynurenine axis mediates hypoxic preconditioning-induced renoprotection; IDO1 deficiency abolishes systemic kynurenine increase and renoprotection from ischemia; exogenous kynurenine restores protection in Ido1-deficient mice, and kynurenine biotransformation preserves NAD+ in post-ischemic kidney.\",\n      \"method\": \"IDO1 knockout mice, serum metabolomics, pharmacological PHD inhibition, exogenous kynurenine administration, kidney ischemia-reperfusion model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (Ido1 KO) combined with metabolomics and metabolite rescue experiment, establishing IDO1 as necessary and sufficient via kynurenine\",\n      \"pmids\": [\"34407414\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IDO1 is a heme-containing dioxygenase that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine via a mechanism in which iron-bound dioxygen abstracts a proton from the substrate (established by crystal structure and mutagenesis); beyond its enzymatic function, phosphorylated ITIM motifs in IDO1 recruit SHP-1 and PI3K to drive non-canonical NF-κB signaling and long-lasting immunosuppression independent of tryptophan catabolism; IDO1 is induced primarily by IFN-γ (and secondarily by IL-6, TLR ligands, and PGE2 via EP2/cAMP signaling) in dendritic cells, MSCs, and tumor cells, where it depletes tryptophan and generates immunosuppressive kynurenines that induce T-cell apoptosis and anergy, shift the Th17/Treg balance, and recruit MDSCs; a kynurenine–AhR autocrine loop maintains long-term IDO1 expression in tolerogenic DCs; IDO1 protein stability is regulated post-translationally by USP14-mediated deubiquitination and is inactivated by peroxynitrite-mediated nitration of Tyr15; under signaling conditions IDO1 translocates from cytosol to early endosomes in a PI3K-dependent manner; and both its enzymatic and non-enzymatic functions contribute independently to tumor immune escape.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IDO1 is a heme-containing dioxygenase that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine, functioning as a central immunoregulatory enzyme whose tryptophan-depleting and kynurenine-generating activities suppress T-cell proliferation, activate the aryl hydrocarbon receptor (AhR) to sustain its own transcription in a positive feedback loop, and promote tolerogenic dendritic cell and regulatory T-cell programs [PMID:15459668, PMID:27316681, PMID:28673995]. Beyond catalysis, IDO1 possesses a non-enzymatic signaling function mediated by phosphorylatable ITIM motifs that recruit SHP-1 and class IA PI3K, activating non-canonical NF-κB in plasmacytoid dendritic cells and Ras/Erk signaling in tumor cells; this signaling mode is spatially regulated by PI3K-dependent translocation of IDO1 from the cytosol to early endosomes [PMID:25215657, PMID:33159421, PMID:36733497]. IDO1 protein stability is post-translationally controlled by the deubiquitinase USP14, and its enzymatic activity is subject to inactivation by peroxynitrite-mediated nitration at Tyr15 [PMID:36163134, PMID:16365430]. Catalytic IDO1 inhibitors such as epacadostat can paradoxically potentiate the non-enzymatic signaling arm, providing a mechanistic explanation for clinical failure of purely catalytic inhibitors [PMID:37122718].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing IDO1 as a tryptophan-catabolizing enzyme central to immune tolerance resolved the question of how dendritic cells suppress T-cell responses across pregnancy, tumors, and infection.\",\n      \"evidence\": \"Synthesis of experimental evidence from multiple in vivo models (pregnancy, tumor, autoimmunity, infection)\",\n      \"pmids\": [\"15459668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of tryptophan depletion vs. kynurenine accumulation not separated\", \"Cell-type specificity of IDO1 vs. IDO2 not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of peroxynitrite-mediated nitration at Tyr15 as a mechanism for IDO1 enzymatic inactivation revealed a post-translational control axis linking nitrosative stress to tryptophan catabolism.\",\n      \"evidence\": \"Recombinant IDO1 treated with peroxynitrite, Tyr-to-Phe mutagenesis, LC/ESI-MS/MS, in-cell immunoprecipitation\",\n      \"pmids\": [\"16365430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of Tyr15 nitration in vivo not demonstrated\", \"Whether nitration is reversible or constitutes permanent inactivation unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that IFN-γ-induced IDO1 expression requires PI3K signaling and is enhanced by IL-4/IL-13 via PP2A clarified the upstream signaling inputs controlling IDO1 transcription in microglia.\",\n      \"evidence\": \"Pharmacological PI3K and PP2A inhibition in primary microglia with cytokine stimulation\",\n      \"pmids\": [\"17661345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PI3K isoform specificity not defined\", \"Direct transcription factor downstream of PI3K not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that intestinal IDO1 induction via TLR-9 depends on IFN/STAT-1 and limits colitis established IDO1 as a tissue-protective, STAT-1-dependent tolerance mechanism in gut inflammation.\",\n      \"evidence\": \"TLR-9 agonist in STAT-1 KO mice with experimental colitis, IDO inhibitor treatment, cell-type expression analysis\",\n      \"pmids\": [\"20181893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IDO1 acts primarily through tryptophan depletion or kynurenine production in the gut not resolved\", \"Contribution of epithelial vs. myeloid IDO1 not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The discovery that IDO1 signals through ITIM phosphorylation to activate non-canonical NF-κB independently of its catalytic activity in pDCs fundamentally expanded the gene's functional repertoire beyond enzymology.\",\n      \"evidence\": \"Forced IDO1 expression in NOD pDCs, NF-κB pathway analysis, autocrine TGF-β measurement, in vivo suppression assay\",\n      \"pmids\": [\"25215657\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for ITIM phosphorylation not identified\", \"Structural basis for ITIM-mediated signaling not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of the IDO1-kynurenine-AhR positive feedback loop explained how transient IFN-γ stimulation leads to sustained tolerogenic IDO1 expression in dendritic cells.\",\n      \"evidence\": \"AhR-KO DCs, pharmacological IDO inhibition, exogenous kynurenine rescue, in vivo tumor-draining lymph node analysis\",\n      \"pmids\": [\"27316681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether kynurenine is the only AhR ligand driving the loop not excluded\", \"Quantitative thresholds for loop engagement unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that IDO1 translocates from cytosol to early endosomes in a class IA PI3K-dependent manner to execute its signaling function provided the first spatial mechanism separating catalytic from non-catalytic roles.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, Co-IP with PI3K subunits, PI3K inhibitor treatment, in vivo pDC phenotype\",\n      \"pmids\": [\"33159421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endosomal signaling partners beyond PI3K not identified\", \"Whether endosomal localization is reversible or terminal not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution of enzyme-null IDO1 in GBM cells showed that non-enzymatic IDO1 drives complement factor H expression, Treg/MDSC recruitment, and reduced survival, establishing that catalytic inhibitors alone cannot neutralize IDO1's tumor-promoting activities.\",\n      \"evidence\": \"WT vs. enzyme-null IDO1 cDNA in IDO1-deficient GBM cells, microarray, syngeneic and humanized mouse models\",\n      \"pmids\": [\"34479957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from IDO1 to CFH transcription not defined\", \"Whether non-enzymatic function operates through ITIMs in tumor cells not confirmed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of USP14 as a deubiquitinase that stabilizes IDO1 protein defined a post-translational control mechanism governing IDO1 abundance and downstream T-cell suppression.\",\n      \"evidence\": \"USP14 overexpression/knockdown, Co-IP/ubiquitination assays, USP14 inhibitor, MC38 syngeneic model with anti-PD-1\",\n      \"pmids\": [\"36163134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase targeting IDO1 for degradation not identified\", \"Specific ubiquitin chain type (K48/K63) on IDO1 not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that the catalytic inhibitor epacadostat paradoxically potentiates IDO1's non-enzymatic signaling arm provided a mechanistic explanation for its clinical failure and redirected therapeutic strategy toward dual-function blockade.\",\n      \"evidence\": \"Cell-based enzymatic vs. signaling readouts in pDCs treated with epacadostat, IDO1 phosphorylation analysis\",\n      \"pmids\": [\"37122718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether all catalytic inhibitors share this paradoxical property not tested\", \"In vivo validation of signaling potentiation by epacadostat lacking\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Enzyme-null but signaling-competent IDO1 (H350A) in melanoma cells activated Ras/Erk to accelerate tumor growth in vivo, directly linking the non-enzymatic arm to a defined oncogenic signaling cascade.\",\n      \"evidence\": \"B16-F10 cells with WT or H350A IDO1, Ras/Erk activity measurement, syngeneic mouse tumors, TIL flow cytometry\",\n      \"pmids\": [\"36733497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IDO1 activates Ras mechanistically is unknown\", \"Whether ITIM-PI3K axis connects to Ras/Erk not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The E3 ubiquitin ligase targeting IDO1 for proteasomal degradation, the kinase phosphorylating IDO1 ITIMs, and the structural basis for how IDO1 activates Ras signaling remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ligase for IDO1 ubiquitination unknown\", \"ITIM kinase identity unresolved\", \"Structural model of IDO1 signaling complex absent\", \"Whether non-enzymatic function contributes to all IDO1-dependent disease contexts untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 9, 20, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 15, 17, 19, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 6, 8, 10, 11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 9, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 15, 23]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"USP14\",\n      \"PIK3CA\",\n      \"PTPN6\",\n      \"AHR\",\n      \"COL12A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IDO1 is a heme-containing dioxygenase that catalyzes the rate-limiting oxidation of L-tryptophan to N-formyl-kynurenine, functioning as a central node of immune regulation by depleting tryptophan and generating immunosuppressive kynurenine-pathway metabolites that induce T-cell apoptosis, promote FoxP3+ regulatory T-cell differentiation, shift the Th17/Treg balance, and recruit myeloid-derived suppressor cells [PMID:12186837, PMID:18832696, PMID:20484731, PMID:26411680]. Its crystal structure reveals two α-helical domains flanking an active-site heme, with iron-bound dioxygen abstracting a proton from L-tryptophan; enzyme activity is induced primarily by IFN-γ (and by IL-6, TLR ligands, and PGE2 via EP2/cAMP), and is sustained through an autocrine kynurenine–AhR positive-feedback loop in dendritic cells [PMID:16477023, PMID:15947091, PMID:27316681]. Beyond catalysis, phosphorylated ITIM motifs in IDO1 recruit SHP-1 and PI3K to activate non-canonical NF-κB signaling and long-lasting immunosuppression independent of tryptophan catabolism; catalytically dead mutants retain the ability to promote tumor immune evasion via Ras/Erk activation, complement factor H upregulation, and altered tumor-infiltrating lymphocyte composition [PMID:25215657, PMID:34145969, PMID:34479957, PMID:36733497]. IDO1 protein stability is regulated by USP14-mediated deubiquitination, and the enzyme is inactivated by peroxynitrite-mediated nitration of Tyr15; under signaling-favoring conditions IDO1 translocates from the cytosol to early endosomes in a PI3K-dependent manner [PMID:36163134, PMID:16365430, PMID:33159421].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The question of whether tryptophan catabolism serves an immunoregulatory role in vivo was answered when pharmacological IDO inhibition caused rapid rejection of allogeneic fetuses, establishing IDO-mediated tryptophan depletion as a mechanism of maternal-fetal immune tolerance.\",\n      \"evidence\": \"1-methyl-tryptophan treatment of pregnant mice with allogeneic fetal survival readout\",\n      \"pmids\": [\"9712583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of T-cell suppression (depletion vs. metabolite toxicity) not resolved\", \"Relative contribution of IDO vs. other tolerance mechanisms at the fetal-maternal interface unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"The cellular mechanism by which IDO suppresses immunity was established: IDO-expressing dendritic cells inhibit T-cell proliferation both by depleting tryptophan and by producing cytotoxic kynurenine metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid), with a constitutively IDO-positive plasmacytoid DC subset identified as a key immunosuppressive population.\",\n      \"evidence\": \"Adenoviral IDO transduction of DCs with metabolite rescue assays; flow cytometry identification of IDO+ pDC subset with in vitro suppression\",\n      \"pmids\": [\"12186837\", \"12228717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of tryptophan depletion vs. kynurenine toxicity in vivo not quantified\", \"Signaling pathways in T cells responding to tryptophan starvation not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Whether tumor cells exploit IDO for immune escape was directly tested: most human tumors constitutively express IDO, IDO-transfected tumor cells prevent T-cell accumulation and rejection, and tumor-draining lymph node pDCs use IDO to induce antigen-specific T-cell anergy.\",\n      \"evidence\": \"IDO expression screening in human tumors; IDO gain-of-function in mouse tumor lines; IDO-KO mice and adoptive transfer in tumor-draining LN pDC system\",\n      \"pmids\": [\"14502282\", \"15254595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDO-mediated anergy is reversible in established tumors not determined\", \"Cell-intrinsic tumor-promoting effects of IDO not explored\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Transcriptional regulation of IDO was delineated: Bin1 loss elevates IDO via STAT1/NF-κB, and PGE2 induces IDO mRNA through EP2/adenylate cyclase but requires a second TLR/TNF signal for enzymatic activation, revealing that IDO induction is a multi-signal integration point.\",\n      \"evidence\": \"Bin1-KO mouse analysis with STAT1/NF-κB pathway dissection; receptor-specific pharmacological antagonism with two-step stimulation protocol in DCs\",\n      \"pmids\": [\"15711557\", \"15947091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-transcriptional regulatory mechanisms not yet characterized\", \"Relative dominance of IFN-γ vs. PGE2 induction in specific tissue contexts undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The catalytic mechanism and post-translational vulnerability of IDO1 were resolved: the 2.3 Å crystal structure showed two α-helical domains flanking a heme group with iron-bound dioxygen abstracting a proton from tryptophan, and peroxynitrite-mediated nitration of Tyr15 was identified as a specific inactivation mechanism.\",\n      \"evidence\": \"X-ray crystallography with active-site mutagenesis; LC/ESI-MS/MS nitration site mapping with Y15F mutant rescue\",\n      \"pmids\": [\"16477023\", \"16365430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full catalytic cycle intermediates not captured crystallographically\", \"Physiological relevance of peroxynitrite inactivation in specific tissues not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The downstream immunological consequence of kynurenine was specified: IDO-expressing pDCs drive generation of FoxP3+ regulatory T cells, and kynurenine itself is sufficient to rescue Treg induction when IDO is pharmacologically blocked.\",\n      \"evidence\": \"TLR9-stimulated human pDCs with IDO inhibitor blocking and kynurenine rescue; Treg suppressor function assays\",\n      \"pmids\": [\"18832696\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kynurenine receptor or sensor on T cells (later identified as AhR) not defined in this study\", \"Relative contribution of different kynurenine catabolites to Treg generation not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The specific kynurenine metabolite mediating Th17/Treg imbalance was identified as 3-hydroxyanthranilic acid, directly linking IDO1 enzymatic output to loss of Th17 cells and reciprocal Treg expansion in progressive HIV infection.\",\n      \"evidence\": \"HIV patient samples combined with in vitro addition of specific tryptophan catabolites to T-cell cultures\",\n      \"pmids\": [\"20484731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether therapeutic IDO inhibition can restore Th17/Treg balance in HIV not tested\", \"Contribution of other kynurenine metabolites to T-cell subset effects not fully dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"IDO was repositioned from a pre-existing tumor escape mechanism to an adaptive feedback response: intratumoral CD8+ T cells drive IDO expression via IFN-γ, and IDO is a critical resistance mechanism to anti-CTLA-4 therapy, as IDO-KO mice show striking synergy with checkpoint blockade.\",\n      \"evidence\": \"T-cell depletion and IFN-γ neutralization in murine tumor models; IDO-KO mice treated with anti-CTLA-4/anti-PD-1/anti-GITR\",\n      \"pmids\": [\"23986400\", \"23752227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IDO inhibitor + checkpoint blockade synergy translates to human tumors not established\", \"Relative importance of tumor-cell vs. host-cell IDO not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A non-enzymatic signaling function of IDO1 was discovered: phosphorylated ITIM motifs recruit SHP-1 and PI3K p110, activating non-canonical NF-κB and autocrine TGF-β production independent of tryptophan catabolism, establishing IDO1 as a dual-function protein.\",\n      \"evidence\": \"ITIM mutant and wild-type IDO1 reconstitution in NOD pDCs with NF-κB pathway analysis and TGF-β measurement\",\n      \"pmids\": [\"25215657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for ITIM phosphorylation not identified\", \"Structural basis for ITIM-mediated signaling complex assembly unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"How IDO expression is maintained long-term without sustained IFN-γ was explained by an autocrine kynurenine–AhR–IDO1 positive feedback loop in DCs, requiring both IDO enzymatic activity and AhR expression for sustained IDO transcription.\",\n      \"evidence\": \"IFN-γ/CD40L-stimulated DCs with IDO inhibitor, kynurenine rescue, and AhR-deficient DC comparison, validated in tumor-bearing mice\",\n      \"pmids\": [\"27316681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the kynurenine-AhR loop operates identically in tumor cells vs. DCs not shown\", \"Chromatin-level mechanism of AhR-driven IDO1 transcription not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The subcellular dynamics of IDO1 signaling function were resolved: under signaling-favoring conditions IDO1 translocates from cytosol to early endosomes in a PI3K-dependent manner, and this relocalization is required for full immunoregulatory function of pDCs in vivo.\",\n      \"evidence\": \"Live-cell imaging, subcellular fractionation, PI3K inhibitors, and in vivo pDC functional assays\",\n      \"pmids\": [\"33159421\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo/adaptor mediating IDO1 endosomal targeting not identified\", \"Whether endosomal IDO1 retains catalytic activity or is exclusively signaling-competent unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The non-enzymatic function was shown to have distinct molecular outputs in tumors: catalytically dead IDO1 upregulates complement factor H/FHL-1 in GBM cells and activates Ras/Erk in melanoma cells, each independently promoting immune evasion and tumor growth.\",\n      \"evidence\": \"Catalytically dead (H350A) IDO1 mutant reconstitution in GBM and B16-F10 cell lines with syngeneic and humanized mouse models\",\n      \"pmids\": [\"34479957\", \"36733497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between ITIM phosphorylation and Ras/Erk or CFH upregulation not mapped\", \"Whether non-enzymatic outputs are tissue/tumor-type specific not systematically tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Post-translational stability regulation of IDO1 was identified: USP14 deubiquitinates IDO1, preventing its proteasomal degradation; USP14 inhibition reduces IDO1 protein levels and reverses T-cell suppression, synergizing with anti-PD-1 therapy.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, USP14 knockdown/pharmacological inhibition in MC38 syngeneic mouse model\",\n      \"pmids\": [\"36163134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase targeting IDO1 for degradation not identified\", \"Whether other deubiquitinases also regulate IDO1 stability not explored\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The clinical failure of the IDO1 catalytic inhibitor epacadostat was mechanistically explained: epacadostat enhances ITIM-mediated non-enzymatic signaling function, potentially potentiating immunosuppression while blocking catalysis.\",\n      \"evidence\": \"ITIM phosphorylation assays and signaling pathway analysis in IDO1-expressing cells treated with epacadostat\",\n      \"pmids\": [\"37122718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Not independently replicated\", \"In vivo validation of enhanced signaling by epacadostat not shown\", \"Whether next-generation inhibitors can block both functions simultaneously not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase(s) that phosphorylate IDO1 ITIMs, the E3 ubiquitin ligase opposing USP14-mediated stabilization, how non-enzymatic signaling outputs differ across tissue and tumor contexts, and whether dual-function (catalytic + signaling) IDO1 inhibitors can achieve clinical immunotherapeutic efficacy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ITIM kinase identity unknown\", \"E3 ligase for IDO1 ubiquitination not identified\", \"No dual-function inhibitor validated in clinical models\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 8, 9, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [17, 22, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [17, 23, 25, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 11, 15, 16, 17, 18, 27]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 8, 13, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 22, 25, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 16, 23, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SHP-1\",\n      \"PIK3CA\",\n      \"USP14\",\n      \"AHR\",\n      \"BIN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}