Affinage

IDO1

Indoleamine 2,3-dioxygenase 1 · UniProt P14902

Round 2 corrected
Length
403 aa
Mass
45.3 kDa
Annotated
2026-04-28
130 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    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

    PMID:9712583

    Open questions at the time
    • 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
  2. 2002 High

    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

    PMID:12186837 PMID:12228717

    Open questions at the time
    • Relative contribution of tryptophan depletion vs. kynurenine toxicity in vivo not quantified
    • Signaling pathways in T cells responding to tryptophan starvation not defined
  3. 2003 High

    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

    PMID:14502282 PMID:15254595

    Open questions at the time
    • Whether IDO-mediated anergy is reversible in established tumors not determined
    • Cell-intrinsic tumor-promoting effects of IDO not explored
  4. 2005 High

    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

    PMID:15711557 PMID:15947091

    Open questions at the time
    • Post-transcriptional regulatory mechanisms not yet characterized
    • Relative dominance of IFN-γ vs. PGE2 induction in specific tissue contexts undefined
  5. 2006 High

    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

    PMID:16365430 PMID:16477023

    Open questions at the time
    • Full catalytic cycle intermediates not captured crystallographically
    • Physiological relevance of peroxynitrite inactivation in specific tissues not established
  6. 2008 High

    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

    PMID:18832696

    Open questions at the time
    • 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
  7. 2010 High

    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

    PMID:20484731

    Open questions at the time
    • 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
  8. 2013 High

    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

    PMID:23752227 PMID:23986400

    Open questions at the time
    • Whether IDO inhibitor + checkpoint blockade synergy translates to human tumors not established
    • Relative importance of tumor-cell vs. host-cell IDO not resolved
  9. 2014 High

    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

    PMID:25215657

    Open questions at the time
    • Kinase responsible for ITIM phosphorylation not identified
    • Structural basis for ITIM-mediated signaling complex assembly unknown
  10. 2016 High

    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

    PMID:27316681

    Open questions at the time
    • Whether the kynurenine-AhR loop operates identically in tumor cells vs. DCs not shown
    • Chromatin-level mechanism of AhR-driven IDO1 transcription not defined
  11. 2020 High

    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

    PMID:33159421

    Open questions at the time
    • Cargo/adaptor mediating IDO1 endosomal targeting not identified
    • Whether endosomal IDO1 retains catalytic activity or is exclusively signaling-competent unknown
  12. 2021 High

    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

    PMID:34479957 PMID:36733497

    Open questions at the time
    • 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
  13. 2022 High

    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

    PMID:36163134

    Open questions at the time
    • E3 ubiquitin ligase targeting IDO1 for degradation not identified
    • Whether other deubiquitinases also regulate IDO1 stability not explored
  14. 2023 Medium

    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

    PMID:37122718

    Open questions at the time
    • Not independently replicated
    • In vivo validation of enhanced signaling by epacadostat not shown
    • Whether next-generation inhibitors can block both functions simultaneously not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • ITIM kinase identity unknown
  • E3 ligase for IDO1 ubiquitination not identified
  • No dual-function inhibitor validated in clinical models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3
Localization
GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 11 R-HSA-1430728 Metabolism 5 R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4
Partners
AHRBIN1PIK3CASHP-1USP14

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. Pharmacological inhibition in vivo (1-methyl-tryptophan treatment of pregnant mice) with fetal survival readout Science High 9712583
2002 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. Flow cytometry cell-surface phenotyping, in vitro T-cell suppression assay with IDO-expressing DC subset Science High 12228717
2002 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. Adenoviral IDO gene transduction of human DCs, in vitro mixed lymphocyte reactions, metabolite supplementation/rescue assays The Journal of experimental medicine High 12186837
2003 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. 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 Nature medicine High 14502282
2004 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. Flow cytometry, adoptive transfer, IDO knockout mice, in vitro suppression assays The Journal of clinical investigation High 15254595
2004 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. IFN-γ stimulation of MSCs, IDO activity measurement (kynurenine production), mixed lymphocyte reactions with tryptophan rescue Blood High 15001472
2005 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. Bin1 knockout mouse studies, STAT1/NF-κB pathway analysis, in vivo tumor regression with IDO inhibitor + chemotherapy combination Nature medicine High 15711557
2005 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. Quantitative IDO mRNA, protein, and enzyme activity assays; pharmacological receptor antagonism; two-step stimulation dissection Blood High 15947091
2006 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. X-ray crystallography of IDO-4-phenylimidazole/cyanide complex; active-site mutagenesis; substrate-binding affinity assays Proceedings of the National Academy of Sciences of the United States of America High 16477023
2006 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. Peroxynitrite treatment of immunoprecipitated and recombinant IDO, nitrotyrosine detection by immunoprecipitation and LC/ESI-MS/MS, Tyr15Phe mutagenesis Journal of immunology High 16365430
2007 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. MSC/NK cell co-culture, IDO inhibitor (1-methyl-tryptophan) and COX inhibitor treatment, flow cytometry of NK receptor expression Blood High 17951526
2008 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. TLR9 stimulation of human pDCs, IDO inhibitor (1-methyl-D-tryptophan) blocking, kynurenine supplementation rescue, Treg suppressor function assays Journal of immunology High 18832696
2009 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. TLR ligand stimulation of MSCs, IFN-β neutralization, PKR pharmacological inhibition, IDO1 activity measurement (kynurenine production) Stem cells High 19353519
2010 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. HIV patient samples (blood and biopsies), in vitro IDO inhibitor experiments, addition of specific tryptophan catabolites to T-cell cultures with Th17/Treg readout Science translational medicine High 20484731
2012 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. Rat chronic pain model, intra-hippocampal IL-6 injection, IDO1 KO mice, pharmacological IDO1 inhibition, HPLC metabolite measurement The Journal of clinical investigation High 22751107
2013 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. Murine tumor models with T-cell depletion and IFN-γ neutralization; correlation of CD8+ T-cell presence with IDO expression in human tumors Science translational medicine High 23986400
2013 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. IDO knockout mouse tumor models, IDO inhibitor + immune checkpoint antibody combination experiments, flow cytometry of tumor-infiltrating immune cells The Journal of experimental medicine High 23752227
2014 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. Transfection of NOD pDCs with IDO1 constructs, NF-κB pathway analysis, TGF-β measurement, cytokine production assays Journal of cellular and molecular medicine High 25215657
2015 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. Syngeneic tumor models with IDO-expressing tumor cells, IDO inhibitor treatment in vivo, flow cytometry of MDSC/Treg populations, functional suppression assays Cell reports High 26411680
2016 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. 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 of immunology High 27316681
2017 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. 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 Proceedings of the National Academy of Sciences of the United States of America High 28673995
2019 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. X-ray crystallography of IDO1-inhibitor complexes, enzyme kinetics, computational modeling Journal of medicinal chemistry High 31525930
2020 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. Live-cell imaging, subcellular fractionation, PI3K inhibitors, in vivo pDC functional assays EMBO reports High 33159421
2021 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. IDO1 enzyme-null mutant reconstitution in GBM cell lines, microarray transcriptomic analysis, syngeneic and humanized mouse models, ex vivo co-culture assays Clinical cancer research High 34479957
2022 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. Co-immunoprecipitation, ubiquitination assays, USP14 knockdown/pharmacological inhibition, MC38 syngeneic mouse model with anti-PD-1 Nature communications High 36163134
2023 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. 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 Oncoimmunology High 36733497
2023 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. ITIM phosphorylation assays, signaling pathway analysis in IDO1-expressing immune cells treated with epacadostat, comparison of enzymatic vs. signaling IDO1 outputs Frontiers in immunology Medium 37122718
2021 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. ITIM mutant constructs, phosphorylation assays, SHP-1/PI3K co-immunoprecipitation, gene expression profiling The FEBS journal High 34145969
2021 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. IDO1 knockout mice, serum metabolomics, pharmacological PHD inhibition, exogenous kynurenine administration, kidney ischemia-reperfusion model Cell reports High 34407414

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Prevention of allogeneic fetal rejection by tryptophan catabolism. Science (New York, N.Y.) 2022 9712583
2003 Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature medicine 1847 14502282
2004 IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nature reviews. Immunology 1836 15459668
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2013 Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Science translational medicine 1445 23986400
2004 Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 1300 15001472
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2005 Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature medicine 889 15711557
2007 Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 871 17951526
2016 IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends in immunology 808 26839260
2002 Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science (New York, N.Y.) 807 12228717
2002 Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. The Journal of experimental medicine 767 12186837
2004 Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. The Journal of clinical investigation 720 15254595
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Tolerance, DCs and tryptophan: much ado about IDO. Trends in immunology 605 12738417
2012 Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer research 575 23090118
2013 Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. The Journal of experimental medicine 538 23752227
2006 Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clinical cancer research : an official journal of the American Association for Cancer Research 523 16489067
2013 Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. Journal of immunology (Baltimore, Md. : 1950) 495 23440412
2010 Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Science translational medicine 443 20484731
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Tumor-Expressed IDO Recruits and Activates MDSCs in a Treg-Dependent Manner. Cell reports 397 26411680
2017 Targeting the IDO1/TDO2-KYN-AhR Pathway for Cancer Immunotherapy - Challenges and Opportunities. Trends in pharmacological sciences 390 29254698
2012 IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clinical cancer research : an official journal of the American Association for Cancer Research 384 22932670
2008 The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. Journal of immunology (Baltimore, Md. : 1950) 380 18832696
2018 Targeting the IDO1 pathway in cancer: from bench to bedside. Journal of hematology & oncology 356 30068361
2006 Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proceedings of the National Academy of Sciences of the United States of America 346 16477023
2005 A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 315 15947091
2015 Cancer Immunotherapy by Targeting IDO1/TDO and Their Downstream Effectors. Frontiers in immunology 298 25628622
2021 Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. Journal of hematology & oncology 280 33883013
2012 Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. The Journal of clinical investigation 276 22751107
2015 Molecular Pathways: Targeting IDO1 and Other Tryptophan Dioxygenases for Cancer Immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 268 26519060
2009 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. Stem cells (Dayton, Ohio) 261 19353519
2005 Biochemical and medical aspects of the indoleamine 2,3-dioxygenase-initiated L-tryptophan metabolism. Biochemical and biophysical research communications 261 16176799
2008 Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 260 18317452
2017 First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies. Clinical cancer research : an official journal of the American Association for Cancer Research 252 28053021
2006 HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 239 17158233
2022 Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer treatment reviews 227 36058143
2014 Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 190 25941578
2013 Network beyond IDO in psychiatric disorders: revisiting neurodegeneration hypothesis. Progress in neuro-psychopharmacology & biological psychiatry 186 24184687
2020 IDO Expression in Cancer: Different Compartment, Different Functionality? Frontiers in immunology 172 33072086
2020 Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Frontiers in immunology 170 32612606
2015 Challenges in the Discovery of Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. Journal of medicinal chemistry 170 25970480
2021 Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme. The FEBS journal 163 34145969
2017 Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival. Clinical cancer research : an official journal of the American Association for Cancer Research 162 28751450
2020 Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 153 32934882
2022 USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer. Nature communications 151 36163134
2020 IDO and Kynurenine Metabolites in Peripheral and CNS Disorders. Frontiers in immunology 151 32194572
2017 Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive 'Cold' Tumors 'Hot'. Trends in cancer 145 29413421
2022 Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process. Ageing research reviews 144 35085834
2014 New Insights into IDO Biology in Bacterial and Viral Infections. Frontiers in immunology 136 25157255
2016 Tolerogenic Phenotype of IFN-γ-Induced IDO+ Dendritic Cells Is Maintained via an Autocrine IDO-Kynurenine/AhR-IDO Loop. Journal of immunology (Baltimore, Md. : 1950) 120 27316681
2007 IL-8 and IDO expression by human gingival fibroblasts via TLRs. Journal of immunology (Baltimore, Md. : 1950) 114 17202379
2020 Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 signaling pathway. Signal transduction and targeted therapy 113 32296044
2019 A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis. Journal of experimental & clinical cancer research : CR 103 31315643
2021 Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 96 34479957
2009 The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. Journal of immunology (Baltimore, Md. : 1950) 96 19494274
2021 Indoleamine 2,3-dioxygenase (Ido) inhibitors and their nanomedicines for cancer immunotherapy. Biomaterials 93 34284200
2018 A patent review of IDO1 inhibitors for cancer. Expert opinion on therapeutic patents 92 29473428
2019 Nanoenabled Reversal of IDO1-Mediated Immunosuppression Synergizes with Immunogenic Chemotherapy for Improved Cancer Therapy. Nano letters 89 31286779
2019 Regorafenib Promotes Antitumor Immunity via Inhibiting PD-L1 and IDO1 Expression in Melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research 88 30940655
2005 Marrying immunotherapy with chemotherapy: why say IDO? Cancer research 88 16166276
2010 Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis. Journal of immunology (Baltimore, Md. : 1950) 86 20181893
2007 Chronic immune activation underlies morbid obesity: is IDO a key player? Current drug metabolism 82 17430117
2007 IDO-expressing regulatory dendritic cells in cancer and chronic infection. Journal of molecular medicine (Berlin, Germany) 81 17876564
2015 Indoleamine 2,3 Dioxygenase (IDO) Expression and Activity in Relapsing-Remitting Multiple Sclerosis. PloS one 78 26110930
2014 The role of IDO in brain tumor immunotherapy. Journal of neuro-oncology 77 25519303
2007 Indoleamine 2,3-dioxygenase (IDO) expression in lung cancer. Cancer biology & therapy 76 17700060
2019 Inhibition Mechanisms of Indoleamine 2,3-Dioxygenase 1 (IDO1). Journal of medicinal chemistry 70 31525930
2023 IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer. The Journal of biological chemistry 68 37196768
2017 Inhibition of acute lethal pulmonary inflammation by the IDO-AhR pathway. Proceedings of the National Academy of Sciences of the United States of America 67 28673995
2021 Tryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO. Frontiers in immunology 66 33708223
2007 On watching the watchers: IDO and type I/II IFN. European journal of immunology 66 17393386
2016 IDO-orchestrated crosstalk between pDCs and Tregs inhibits autoimmunity. Journal of autoimmunity 65 27470005
2014 Immunological Relevance of the Coevolution of IDO1 and AHR. Frontiers in immunology 63 25368620
2011 The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer. Current medicinal chemistry 62 21517752
2010 Towards a genetic definition of cancer-associated inflammation: role of the IDO pathway. The American journal of pathology 62 20228228
2015 A Review: Phytochemicals Targeting JAK/STAT Signaling and IDO Expression in Cancer. Phytotherapy research : PTR 61 25787773
2015 Interferon Lambda Upregulates IDO1 Expression in Respiratory Epithelial Cells After Influenza Virus Infection. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 60 25756191
2011 Identification of IDO-positive and IDO-negative human dendritic cells after activation by various proinflammatory stimuli. Journal of immunology (Baltimore, Md. : 1950) 58 21543643
2006 Nitration and inactivation of IDO by peroxynitrite. Journal of immunology (Baltimore, Md. : 1950) 58 16365430
2023 Paraptosis Inducer to Effectively Trigger Immunogenic Cell Death for Metastatic Tumor Immunotherapy with IDO Inhibition. ACS nano 57 37200049
2018 Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 57 29980987
2021 Necrostatin-1 Prevents Ferroptosis in a RIPK1- and IDO-Independent Manner in Hepatocellular Carcinoma. Antioxidants (Basel, Switzerland) 56 34572979
2018 PD-L1 and IDO1 Are Expressed in Poorly Differentiated Thyroid Carcinoma. Endocrine pathology 56 29372535
2012 The indoleamine 2,3-dioxygenase (IDO) pathway controls allergy. Allergy 53 22519427
2023 Self-driven nanoprodrug platform with enhanced ferroptosis for synergistic photothermal-IDO immunotherapy. Biomaterials 51 37196407
2017 Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl hydrocarbon receptor. Toxicology and applied pharmacology 50 28336214
2014 Forced IDO1 expression in dendritic cells restores immunoregulatory signalling in autoimmune diabetes. Journal of cellular and molecular medicine 50 25215657
2007 Tryptophan catabolism in IDO+ plasmacytoid dendritic cells. Current drug metabolism 49 17430109
2007 IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia 49 17661345
2024 Light-Triggered PROTAC Nanoassemblies for Photodynamic IDO Proteolysis in Cancer Immunotherapy. Advanced materials (Deerfield Beach, Fla.) 48 38898702
2019 IDO activation, inflammation and musculoskeletal disease. Experimental gerontology 48 31884118
2010 Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin. European journal of neurology 47 21118329
2019 Multiple myeloma cell-derived IL-32γ increases the immunosuppressive function of macrophages by promoting indoleamine 2,3-dioxygenase (IDO) expression. Cancer letters 46 30660652
2011 Regulation of expression and function of IDO in human dendritic cells. Current medicinal chemistry 45 21517757
2018 IDO1 impairs NK cell cytotoxicity by decreasing NKG2D/NKG2DLs via promoting miR-18a. Molecular immunology 43 30268986
2016 IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma. Oncotarget 41 27174915
2021 Tryptophan metabolism in brain tumors - IDO and beyond. Current opinion in immunology 40 33813026
2007 Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. Current drug metabolism 40 17430113
2014 AhR-Mediated, Non-Genomic Modulation of IDO1 Function. Frontiers in immunology 39 25360135
2006 DFT-INDO/S modeling of new high molar extinction coefficient charge-transfer sensitizers for solar cell applications. Inorganic chemistry 39 16411715
2019 4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors. Bioorganic & medicinal chemistry 36 30773421
2022 Impact of IDO1 and IDO2 on the B Cell Immune Response. Frontiers in immunology 35 35493480
2022 Dual-target inhibitors of indoleamine 2, 3 dioxygenase 1 (Ido1): A promising direction in cancer immunotherapy. European journal of medicinal chemistry 34 35696861
2017 Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism. Journal of immunology (Baltimore, Md. : 1950) 34 28264972
2023 Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4+CD25+Foxp3+Tregs through IDO-Kyn-AHR axis. International immunopharmacology 33 36706593
2021 Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway. Cell reports 33 34407414
2020 Class IA PI3Ks regulate subcellular and functional dynamics of IDO1. EMBO reports 32 33159421
2023 PCSK9 Inhibition Reduces Depressive like Behavior in CUMS-Exposed Rats: Highlights on HMGB1/RAGE/TLR4 Pathway, NLRP3 Inflammasome Complex and IDO-1. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 31 36781714
2020 FoxP3, CTLA-4, and IDO in Canine Melanocytic Tumors. Veterinary pathology 31 33021155
2018 Design, synthesis and biological evaluation of novel naphthoquinone derivatives as IDO1 inhibitors. European journal of medicinal chemistry 31 30103191
2015 IDO Downregulation Induces Sensitivity to Pemetrexed, Gemcitabine, FK866, and Methoxyamine in Human Cancer Cells. PloS one 31 26579709
2014 S100A4 and uric acid promote mesenchymal stromal cell induction of IL-10+/IDO+ lymphocytes. Journal of immunology (Baltimore, Md. : 1950) 31 24795458
2023 DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota. Frontiers in immunology 30 36776388
2022 Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1. Neuro-oncology advances 30 35990703
2023 An adverse tumor-protective effect of IDO1 inhibition. Cell reports. Medicine 28 36812891
2020 Expression of Indoleamine 2, 3-dioxygenase 1 (IDO1) and Tryptophanyl-tRNA Synthetase (WARS) in Gastric Cancer Molecular Subtypes. Applied immunohistochemistry & molecular morphology : AIMM 28 31033497
2019 Carboxyamidotriazole combined with IDO1-Kyn-AhR pathway inhibitors profoundly enhances cancer immunotherapy. Journal for immunotherapy of cancer 28 31511064
2021 Structure and Plasticity of Indoleamine 2,3-Dioxygenase 1 (IDO1). Journal of medicinal chemistry 26 34907770
2019 Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. MedChemComm 26 32055299
2020 IDO Targeting in Sarcoma: Biological and Clinical Implications. Frontiers in immunology 25 32194552
2023 The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1. Frontiers in immunology 24 37122718
2019 Effects of IDO1 and TDO2 inhibition on cognitive deficits and anxiety following LPS-induced neuroinflammation. Acta neuropsychiatrica 24 31753057
2018 FoxP3 and IDO in Canine Melanocytic Tumors. Veterinary pathology 24 30381008
2023 The signaling function of IDO1 incites the malignant progression of mouse B16 melanoma. Oncoimmunology 23 36733497
2024 Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1. Cell communication and signaling : CCS 22 39061097