{"gene":"FOLR2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2020,"finding":"FOLR2 gene expression in macrophages is transcriptionally regulated by the PU.1 transcription factor. PU.1-binding elements were identified upstream of the first exon of FOLR2, and siRNA-mediated knockdown of PU.1 reduced FOLR2 expression in myeloid cells. Functional analysis of the proximal regulatory region of FOLR2 confirmed dependence on a cluster of PU.1-binding sequences.","method":"siRNA knockdown, luciferase reporter assay of FOLR2 proximal regulatory region, bioinformatic identification of PU.1-binding elements","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown combined with luciferase reporter assay in a single lab, two orthogonal methods establishing PU.1 dependence","pmids":["32532019"],"is_preprint":false},{"year":2022,"finding":"FOLR2+ tissue-resident macrophages localize in perivascular areas of the tumor stroma in breast cancer, where they physically interact with CD8+ T cells and efficiently prime effector CD8+ T cells ex vivo.","method":"Immunofluorescence localization, ex vivo co-culture priming assay, flow cytometry","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (ex vivo priming), single lab with multiple orthogonal methods","pmids":["35325594"],"is_preprint":false},{"year":2016,"finding":"FRβ (FOLR2 protein) is expressed on mature myeloid-lineage hematopoietic cells (including CD14+ monocytes) but is nearly undetectable on CD34+ hematopoietic stem cells, as determined using a high-affinity (2.48 nM KD) FRβ-specific antibody. CAR T cells targeting FRβ lysed mature CD14+ monocytes while leaving HSC colony formation unaffected.","method":"Flow cytometry with high-affinity FRβ-specific antibody, in vitro cytotoxicity assay, HSC colony formation assay, in vivo xenograft model","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro and in vivo assays in a single lab demonstrating cell-type-specific expression with functional consequence","pmids":["26898190"],"is_preprint":false},{"year":2024,"finding":"FOLR2 expression on macrophages is regulated during M-CSF-driven differentiation in skin via intrinsic STAT6 and ALK5 activity, without requiring heterotypic cellular crosstalk. In contrast, CD163 co-expression on the same FRβ/CD163+ S1 macrophage subset requires fibroblast-derived signals (laminin-α2 and type-V collagen) through an SHP1/STAT5-dependent pathway.","method":"Single-cell transcriptomics, flow cytometry, coculture experiments with fibroblasts, in silico ligand expression analysis, pharmacological inhibition of STAT6/ALK5/SHP1","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (coculture, inhibitor experiments, scRNA-seq) in a single lab establishing distinct regulatory mechanisms for FRβ vs CD163","pmids":["39720957"],"is_preprint":false},{"year":2024,"finding":"FOLR2+ macrophages promote fibrosis in chronic kidney disease through a WNT/β-catenin-dependent pathway: inflammatory fibroblasts (CXCL-iFibro) attract and accumulate FOLR2+ macrophages, which in turn drive the switch of CXCL-iFibro into ECM-secreting myofibroblasts via WNT/β-catenin signaling.","method":"In vitro macrophage-fibroblast coculture, WNT/β-catenin pathway analysis, single-cell transcriptomics, multiplex immunohistochemistry","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro coculture with pathway-level mechanistic follow-up (WNT/β-catenin), single lab with multiple orthogonal methods","pmids":["38272907"],"is_preprint":false},{"year":2018,"finding":"Silencing of FOLR2 in the NCI-H1650 non-small cell lung cancer cell line inhibited phosphorylation of AKT, mTOR, and S6K1, reduced cell viability, arrested cells in G1 phase, decreased cyclin D1, and increased Bax/Bcl-2 ratio and apoptosis.","method":"siRNA-mediated gene knockdown, Western blot, CCK-8 viability assay, flow cytometry (cell cycle and apoptosis)","journal":"Medical science monitor","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single knockdown approach with downstream readouts but no mechanistic reconstitution or rescue experiment; context (NSCLC cell line) may not reflect canonical FRβ biology","pmids":["30415267"],"is_preprint":false},{"year":2025,"finding":"FOLR2+ macrophages in breast cancer activate CD8+ T cell cytotoxicity through the CXCL9-CXCR3 axis. FOLR2+ macrophages secrete CXCL9 which engages CXCR3 on CD8+ T cells, and animal experiments confirmed this axis mediates the antitumor effect of FOLR2+ macrophages.","method":"Single-cell RNA sequencing, bulk RNA sequencing, in vitro coculture, in vivo mouse experiments","journal":"Breast cancer research : BCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments combined with transcriptomic data in a single lab establishing the CXCL9-CXCR3 mechanistic axis","pmids":["40045365"],"is_preprint":false},{"year":2024,"finding":"FOLR2+ macrophages activate CD8+ T cell cytotoxicity via antigen cross-presentation in gastric cancer progression. Epithelial cells induce necroptosis of FOLR2+ macrophages via the APP-TNFRSF21 axis, reducing their proportion from complete intestinal metaplasia to early gastric cancer.","method":"Single-cell RNA sequencing, multiplex immunohistochemical staining, in vitro coculture of FOLR2+/FOLR2- macrophages with CD8+ T cells, flow cytometry","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro coculture experiments with functional readout (CD8+ T cell cytotoxicity) and mechanistic pathway (APP-TNFRSF21 necroptosis), single lab","pmids":["39702278"],"is_preprint":false},{"year":2025,"finding":"FOLR2+ macrophages in gastric cancer suppress CD8+ T cell function by expressing PD-L1 and secreting IL-10. Disruption of IL-10 sensitizes anti-PD-1 blockade and promotes antitumor immunity in FOLR2+ TAM-high tumors, demonstrated in fresh tumor tissue culture.","method":"In vitro culture of fresh tumor tissue, multiplex immunohistochemistry, transcriptional data analysis","journal":"International journal of surgery (London, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, ex vivo tumor culture without full mechanistic reconstitution; functional pathway (IL-10-mediated CD8+ T cell suppression) partially established","pmids":["41263393"],"is_preprint":false},{"year":2024,"finding":"miR-622 directly targets FOLR2 mRNA to promote colorectal cancer cell proliferation. FOLR2 was validated as a functional target of miR-622 via dual luciferase assay; FOLR2 negatively correlates with cell cycle gene signatures, and its suppression by miR-622 drives cell cycle progression.","method":"Dual luciferase reporter assay, gain-of-function and loss-of-function experiments in vitro and in vivo, bioinformatics","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus in vitro and in vivo functional experiments, single lab","pmids":["38166756"],"is_preprint":false},{"year":2025,"finding":"CLL cells acquire functional FOLR2 protein from nurse-like cells (NLCs) via trogocytosis, enhancing their folate uptake. FOLR2+ CLL cells (those that acquired FOLR2 by trogocytosis) are the predominant actively cycling cancer cell population. This was confirmed by multiplex immunofluorescence in CLL patient lymph nodes.","method":"Primary patient cell coculture, flow cytometry, multiplex immunofluorescence of lymph node biopsies, proliferation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, trogocytosis mechanism inferred from correlative and coculture data without direct mechanistic reconstitution","pmids":[],"is_preprint":true},{"year":2024,"finding":"FOLR2-encoded folate receptor beta (FRβ) was predicted and experimentally validated to bind PFNA, PFOA, and PFOS (but not PFHxS, PFBS, or GenX) by in vitro protein binding analysis, correlating with their in vivo neurodevelopmental toxicity in zebrafish.","method":"Reverse molecular docking (computational), in vitro protein binding assay, in vivo zebrafish loss-of-function and rescue experiments","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab; in vitro binding validated but mechanistic link between FRβ binding and neurotoxicity is inferential; zebrafish ortholog used","pmids":[],"is_preprint":true},{"year":2026,"finding":"In aging mouse testes, FOLR2+ resident macrophages undergo a phenotypic transition toward a pro-inflammatory state driven by mitochondrial metabolic dysfunction, specifically inhibition of IDH2 (a TCA cycle enzyme). This transition facilitates recruitment of monocytes and CD8+ T cells via the CCL8-CCR2/CCR5 axis.","method":"Single-cell RNA sequencing, multiplex immunofluorescence, IDH2 inhibition experiments","journal":"GeroScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, IDH2 inhibition mechanistic link is pharmacological without genetic reconstitution; CCL8-CCR2/CCR5 axis inferred from transcriptomics","pmids":["41618065"],"is_preprint":false}],"current_model":"FOLR2 encodes folate receptor beta (FRβ), a GPI-anchored folate-binding protein expressed predominantly on tissue-resident macrophages, where its transcription is driven by the PU.1 transcription factor; FOLR2+ macrophages localize in perivascular stromal areas and interact with CD8+ T cells via antigen cross-presentation and the CXCL9-CXCR3 axis to promote antitumor immunity, while in some contexts they can suppress T cell function through PD-L1 and IL-10; their differentiation in skin requires STAT6/ALK5-dependent intrinsic signals for FRβ expression and fibroblast-derived laminin/collagen signals (via SHP1/STAT5) for CD163 co-expression; in CKD, FOLR2+ macrophages promote myofibroblast differentiation through WNT/β-catenin signaling; and the protein functions as a bona fide folate uptake receptor that can be transferred between cells by trogocytosis."},"narrative":{"mechanistic_narrative":"FOLR2 encodes folate receptor beta (FRβ), a folate-binding protein that functions as a folate uptake receptor and serves as a defining marker of tissue-resident macrophages, in which it is expressed on mature myeloid cells but not on CD34+ hematopoietic stem cells [PMID:26898190]. Its transcription in myeloid cells is driven by the PU.1 transcription factor acting through a cluster of PU.1-binding elements upstream of the first exon [PMID:32532019], and during M-CSF-driven macrophage differentiation in skin FRβ expression depends on intrinsic STAT6/ALK5 signaling, with co-expressed markers such as CD163 instead requiring fibroblast-derived laminin/collagen cues via an SHP1/STAT5 pathway [PMID:39720957]. FOLR2+ macrophages occupy perivascular tumor stroma where they prime and activate CD8+ T cell cytotoxicity through antigen cross-presentation and the CXCL9-CXCR3 axis, supporting antitumor immunity [PMID:35325594, PMID:40045365, PMID:39702278]. In other contexts these macrophages drive tissue remodeling, promoting myofibroblast differentiation in chronic kidney disease through WNT/β-catenin signaling [PMID:38272907]. The folate-binding protein itself can be transferred between cells, with malignant cells acquiring functional FRβ by trogocytosis to enhance folate uptake.","teleology":[{"year":2016,"claim":"Establishing where FRβ protein is and is not expressed defined its value as a lineage-restricted target, distinguishing mature myeloid cells from hematopoietic progenitors.","evidence":"Flow cytometry with a high-affinity FRβ antibody plus CAR T cytotoxicity and HSC colony assays in vitro and in xenografts","pmids":["26898190"],"confidence":"Medium","gaps":["Does not address folate-binding function of FRβ","Expression pattern in non-myeloid tissues not defined"]},{"year":2018,"claim":"A knockdown screen in a lung cancer line linked FOLR2 to PI3K/AKT/mTOR signaling and proliferation, raising a possible cell-intrinsic oncogenic role.","evidence":"siRNA knockdown with Western blot, viability, cell cycle and apoptosis readouts in NCI-H1650 cells","pmids":["30415267"],"confidence":"Low","gaps":["No rescue or reconstitution experiment","NSCLC cell line context may not reflect canonical FRβ macrophage biology","Mechanism connecting FRβ to AKT/mTOR unestablished"]},{"year":2020,"claim":"Identifying PU.1 as the transcriptional driver explained why FOLR2 is restricted to the myeloid lineage.","evidence":"siRNA knockdown of PU.1 plus luciferase reporter analysis of the FOLR2 proximal regulatory region","pmids":["32532019"],"confidence":"Medium","gaps":["Other co-regulators of macrophage-specific expression not defined","Does not address signal-dependent tuning of expression"]},{"year":2022,"claim":"Localizing FOLR2+ macrophages to perivascular tumor stroma and showing they prime CD8+ T cells reframed FRβ+ macrophages as immunostimulatory players in the tumor microenvironment.","evidence":"Immunofluorescence localization and ex vivo CD8+ T cell priming coculture in breast cancer","pmids":["35325594"],"confidence":"Medium","gaps":["Molecular mechanism of priming not resolved here","Causal contribution to tumor control in vivo not shown"]},{"year":2024,"claim":"Dissecting FRβ versus CD163 induction during macrophage differentiation separated cell-intrinsic from microenvironmental control of the FRβ+ macrophage phenotype.","evidence":"scRNA-seq, fibroblast coculture, and pharmacological inhibition of STAT6/ALK5/SHP1 in skin macrophages","pmids":["39720957"],"confidence":"Medium","gaps":["Direct STAT6/ALK5 binding at the FOLR2 locus not shown","Generalizability beyond skin macrophages untested"]},{"year":2024,"claim":"Showing FOLR2+ macrophages drive fibroblast-to-myofibroblast conversion via WNT/β-catenin identified a pro-fibrotic, tissue-remodeling role distinct from their immune functions.","evidence":"Macrophage-fibroblast coculture, WNT/β-catenin pathway analysis, scRNA-seq and multiplex IHC in chronic kidney disease","pmids":["38272907"],"confidence":"Medium","gaps":["WNT ligand source and identity not defined","In vivo genetic depletion not performed"]},{"year":2024,"claim":"Identifying FOLR2 as a direct miR-622 target connected its loss to cell cycle progression in colorectal cancer.","evidence":"Dual luciferase target validation with gain- and loss-of-function experiments in vitro and in vivo","pmids":["38166756"],"confidence":"Medium","gaps":["Whether FRβ acts cell-intrinsically in tumor cells or via macrophages unclear","Mechanism of cell cycle suppression by FRβ not defined"]},{"year":2024,"claim":"Demonstrating antigen cross-presentation by FOLR2+ macrophages and their epithelial-driven necroptosis tied their abundance to gastric cancer progression.","evidence":"scRNA-seq, multiplex IHC, FOLR2+/FOLR2- macrophage-CD8+ T cell cocultures in gastric cancer","pmids":["39702278"],"confidence":"Medium","gaps":["APP-TNFRSF21 necroptosis axis correlative","Antigen specificity of cross-presentation not characterized"]},{"year":2025,"claim":"Defining the CXCL9-CXCR3 axis provided the molecular mechanism by which FOLR2+ macrophages activate CD8+ T cell cytotoxicity and mediate antitumor effects.","evidence":"scRNA-seq, bulk RNA-seq, coculture, and in vivo mouse experiments in breast cancer","pmids":["40045365"],"confidence":"Medium","gaps":["Upstream signals inducing CXCL9 secretion not resolved","Reconciliation with immunosuppressive contexts not addressed"]},{"year":2025,"claim":"Showing FOLR2+ macrophages can also suppress CD8+ T cells via PD-L1 and IL-10 revealed context-dependent, opposing immune functions.","evidence":"Ex vivo fresh tumor tissue culture, multiplex IHC and transcriptional analysis in gastric cancer","pmids":["41263393"],"confidence":"Low","gaps":["No full mechanistic reconstitution of IL-10/PD-L1 suppression","Conflicts with stimulatory roles reported elsewhere remain unreconciled"]},{"year":2025,"claim":"Trogocytic transfer of functional FRβ from nurse-like cells to CLL cells linked the receptor's folate-uptake function to cancer cell proliferation.","evidence":"Primary patient cell coculture, flow cytometry, and multiplex immunofluorescence of CLL lymph nodes (preprint)","pmids":[],"confidence":"Low","gaps":["Trogocytosis mechanism inferred from correlative coculture data","Preprint, not independently confirmed","Direct demonstration of folate flux through transferred receptor incomplete"]},{"year":2026,"claim":"Linking IDH2-driven mitochondrial dysfunction to a pro-inflammatory shift in testicular FOLR2+ macrophages connected metabolic state to their phenotypic plasticity in aging.","evidence":"scRNA-seq, multiplex immunofluorescence, and pharmacological IDH2 inhibition in aging mouse testes","pmids":["41618065"],"confidence":"Low","gaps":["IDH2 link is pharmacological without genetic reconstitution","CCL8-CCR2/CCR5 recruitment axis inferred from transcriptomics"]},{"year":null,"claim":"How FRβ's folate-binding biochemistry mechanistically governs the divergent immunostimulatory versus immunosuppressive and pro-fibrotic behaviors of FOLR2+ macrophages remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of FRβ ligand binding in the corpus","Context determinants of stimulatory vs suppressive macrophage states undefined","Whether folate uptake itself drives macrophage phenotype is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[2,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6,7]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14207","full_name":"Folate receptor beta","aliases":["Folate receptor 2","Folate receptor, fetal/placental","Placental folate-binding protein","FBP"],"length_aa":255,"mass_kda":29.3,"function":"Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells. Has high affinity for folate and folic acid analogs at neutral pH. Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release","subcellular_location":"Cell membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P14207/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOLR2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":383,"dependency_fraction":0.010443864229765013},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FOLR2","total_profiled":1310},"omim":[{"mim_id":"608630","title":"ROUNDABOUT GUIDANCE RECEPTOR 3; ROBO3","url":"https://www.omim.org/entry/608630"},{"mim_id":"607313","title":"GAZE PALSY, FAMILIAL HORIZONTAL, WITH PROGRESSIVE SCOLIOSIS 1; HGPPS1","url":"https://www.omim.org/entry/607313"},{"mim_id":"602469","title":"FOLATE RECEPTOR 3; FOLR3","url":"https://www.omim.org/entry/602469"},{"mim_id":"136430","title":"FOLATE RECEPTOR, ALPHA; FOLR1","url":"https://www.omim.org/entry/136430"},{"mim_id":"136425","title":"FOLATE RECEPTOR, BETA; FOLR2","url":"https://www.omim.org/entry/136425"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":158.2}],"url":"https://www.proteinatlas.org/search/FOLR2"},"hgnc":{"alias_symbol":["FRβ"],"prev_symbol":[]},"alphafold":{"accession":"P14207","domains":[{"cath_id":"-","chopping":"27-152_166-255","consensus_level":"medium","plddt":91.7329,"start":27,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14207","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14207-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14207-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOLR2","jax_strain_url":"https://www.jax.org/strain/search?query=FOLR2"},"sequence":{"accession":"P14207","fasta_url":"https://rest.uniprot.org/uniprotkb/P14207.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14207/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14207"}},"corpus_meta":[{"pmid":"35325594","id":"PMC_35325594","title":"Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer.","date":"2022","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/35325594","citation_count":456,"is_preprint":false},{"pmid":"26898190","id":"PMC_26898190","title":"High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.","date":"2016","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/26898190","citation_count":108,"is_preprint":false},{"pmid":"38272907","id":"PMC_38272907","title":"WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38272907","citation_count":49,"is_preprint":false},{"pmid":"32532019","id":"PMC_32532019","title":"Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32532019","citation_count":41,"is_preprint":false},{"pmid":"36122412","id":"PMC_36122412","title":"A Population of TIM4+FOLR2+ Macrophages Localized in Tertiary Lymphoid Structures Correlates to an Active Immune Infiltrate Across Several Cancer Types.","date":"2022","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/36122412","citation_count":40,"is_preprint":false},{"pmid":"20683905","id":"PMC_20683905","title":"Association of folate receptor (FOLR1, FOLR2, FOLR3) and reduced folate carrier (SLC19A1) genes with meningomyelocele.","date":"2010","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/20683905","citation_count":34,"is_preprint":false},{"pmid":"37532692","id":"PMC_37532692","title":"Single-cell profiling reveals the trajectory of FOLR2-expressing tumor-associated macrophages to regulatory T cells in the progression of lung adenocarcinoma.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37532692","citation_count":32,"is_preprint":false},{"pmid":"22094710","id":"PMC_22094710","title":"Macrophage folate receptor-β (FR-β) expression in auto-immune inflammatory rheumatic diseases: a forthcoming marker for cardiovascular risk?","date":"2011","source":"Autoimmunity reviews","url":"https://pubmed.ncbi.nlm.nih.gov/22094710","citation_count":32,"is_preprint":false},{"pmid":"39702278","id":"PMC_39702278","title":"FOLR2+ macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer 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BCR","url":"https://pubmed.ncbi.nlm.nih.gov/40045365","citation_count":8,"is_preprint":false},{"pmid":"39105761","id":"PMC_39105761","title":"Folate Receptor β (FRβ) Expression on Myeloid Cells and the Impact of Reticuloendothelial System on Folate-Functionalized Nanoparticles' Biodistribution in Cancer.","date":"2024","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/39105761","citation_count":8,"is_preprint":false},{"pmid":"40457348","id":"PMC_40457348","title":"FOLR2+ macrophages in cancer: allies or enemies.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40457348","citation_count":7,"is_preprint":false},{"pmid":"39720957","id":"PMC_39720957","title":"Guided monocyte fate to FRβ/CD163+ S1 macrophage antagonises atopic dermatitis via fibroblastic matrices in mouse hypodermis.","date":"2024","source":"Cellular and molecular life sciences : 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biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/37883728","citation_count":1,"is_preprint":false},{"pmid":"41618065","id":"PMC_41618065","title":"Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging.","date":"2026","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/41618065","citation_count":1,"is_preprint":false},{"pmid":"35545363","id":"PMC_35545363","title":"Association of periconceptional folate supplements and FOLR1 and FOLR2 gene polymorphisms with risk of congenital heart disease in offspring: A hospital-based case-control study.","date":"2022","source":"Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35545363","citation_count":0,"is_preprint":false},{"pmid":"40791604","id":"PMC_40791604","title":"CD4+ skin resident memory T cells preferentially colocalize with dermal Folr2hi macrophages in contact hypersensitivity.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40791604","citation_count":0,"is_preprint":false},{"pmid":"40219974","id":"PMC_40219974","title":"Design and Synthesis of FR-β Targeting Chimeric Molecules for Reprogramming Tumor-Associated Macrophages Using 6-Substituted Pyrrolo[2,3-d]pyrimidines as Targeting Ligands.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/40219974","citation_count":0,"is_preprint":false},{"pmid":"41727129","id":"PMC_41727129","title":"2-Deoxyglucose dendrimer-enabled niclosamide delivery to FRβ-expressing macrophages alleviates endometriosis progression and associated hyperalgesia.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41727129","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.30.657106","title":"Spatial Heterogeneity of Macrophages in the Human Lung","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.657106","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.31.630890","title":"Trogocytosis-mediated transfer of FOLR2 from nurse-like cells to CLL cells is associated with their activation and proliferation","date":"2025-01-02","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.31.630890","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.11.623082","title":"Proteome-wide reverse molecular docking reveals folate receptor as a mediator of PFAS-induced neurodevelopmental toxicity","date":"2024-11-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.11.623082","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.06.24.600550","title":"Lipidic and senescent macrophages predict progression and response to combinatorial immunotherapy in triple-negative breast cancer","date":"2024-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600550","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17777,"output_tokens":3415,"usd":0.052278,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11030,"output_tokens":3541,"usd":0.071837,"stage2_stop_reason":"end_turn"},"total_usd":0.124115,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"FOLR2 gene expression in macrophages is transcriptionally regulated by the PU.1 transcription factor. PU.1-binding elements were identified upstream of the first exon of FOLR2, and siRNA-mediated knockdown of PU.1 reduced FOLR2 expression in myeloid cells. Functional analysis of the proximal regulatory region of FOLR2 confirmed dependence on a cluster of PU.1-binding sequences.\",\n      \"method\": \"siRNA knockdown, luciferase reporter assay of FOLR2 proximal regulatory region, bioinformatic identification of PU.1-binding elements\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown combined with luciferase reporter assay in a single lab, two orthogonal methods establishing PU.1 dependence\",\n      \"pmids\": [\"32532019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOLR2+ tissue-resident macrophages localize in perivascular areas of the tumor stroma in breast cancer, where they physically interact with CD8+ T cells and efficiently prime effector CD8+ T cells ex vivo.\",\n      \"method\": \"Immunofluorescence localization, ex vivo co-culture priming assay, flow cytometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (ex vivo priming), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35325594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FRβ (FOLR2 protein) is expressed on mature myeloid-lineage hematopoietic cells (including CD14+ monocytes) but is nearly undetectable on CD34+ hematopoietic stem cells, as determined using a high-affinity (2.48 nM KD) FRβ-specific antibody. CAR T cells targeting FRβ lysed mature CD14+ monocytes while leaving HSC colony formation unaffected.\",\n      \"method\": \"Flow cytometry with high-affinity FRβ-specific antibody, in vitro cytotoxicity assay, HSC colony formation assay, in vivo xenograft model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro and in vivo assays in a single lab demonstrating cell-type-specific expression with functional consequence\",\n      \"pmids\": [\"26898190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOLR2 expression on macrophages is regulated during M-CSF-driven differentiation in skin via intrinsic STAT6 and ALK5 activity, without requiring heterotypic cellular crosstalk. In contrast, CD163 co-expression on the same FRβ/CD163+ S1 macrophage subset requires fibroblast-derived signals (laminin-α2 and type-V collagen) through an SHP1/STAT5-dependent pathway.\",\n      \"method\": \"Single-cell transcriptomics, flow cytometry, coculture experiments with fibroblasts, in silico ligand expression analysis, pharmacological inhibition of STAT6/ALK5/SHP1\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (coculture, inhibitor experiments, scRNA-seq) in a single lab establishing distinct regulatory mechanisms for FRβ vs CD163\",\n      \"pmids\": [\"39720957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOLR2+ macrophages promote fibrosis in chronic kidney disease through a WNT/β-catenin-dependent pathway: inflammatory fibroblasts (CXCL-iFibro) attract and accumulate FOLR2+ macrophages, which in turn drive the switch of CXCL-iFibro into ECM-secreting myofibroblasts via WNT/β-catenin signaling.\",\n      \"method\": \"In vitro macrophage-fibroblast coculture, WNT/β-catenin pathway analysis, single-cell transcriptomics, multiplex immunohistochemistry\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro coculture with pathway-level mechanistic follow-up (WNT/β-catenin), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38272907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Silencing of FOLR2 in the NCI-H1650 non-small cell lung cancer cell line inhibited phosphorylation of AKT, mTOR, and S6K1, reduced cell viability, arrested cells in G1 phase, decreased cyclin D1, and increased Bax/Bcl-2 ratio and apoptosis.\",\n      \"method\": \"siRNA-mediated gene knockdown, Western blot, CCK-8 viability assay, flow cytometry (cell cycle and apoptosis)\",\n      \"journal\": \"Medical science monitor\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single knockdown approach with downstream readouts but no mechanistic reconstitution or rescue experiment; context (NSCLC cell line) may not reflect canonical FRβ biology\",\n      \"pmids\": [\"30415267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOLR2+ macrophages in breast cancer activate CD8+ T cell cytotoxicity through the CXCL9-CXCR3 axis. FOLR2+ macrophages secrete CXCL9 which engages CXCR3 on CD8+ T cells, and animal experiments confirmed this axis mediates the antitumor effect of FOLR2+ macrophages.\",\n      \"method\": \"Single-cell RNA sequencing, bulk RNA sequencing, in vitro coculture, in vivo mouse experiments\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments combined with transcriptomic data in a single lab establishing the CXCL9-CXCR3 mechanistic axis\",\n      \"pmids\": [\"40045365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOLR2+ macrophages activate CD8+ T cell cytotoxicity via antigen cross-presentation in gastric cancer progression. Epithelial cells induce necroptosis of FOLR2+ macrophages via the APP-TNFRSF21 axis, reducing their proportion from complete intestinal metaplasia to early gastric cancer.\",\n      \"method\": \"Single-cell RNA sequencing, multiplex immunohistochemical staining, in vitro coculture of FOLR2+/FOLR2- macrophages with CD8+ T cells, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro coculture experiments with functional readout (CD8+ T cell cytotoxicity) and mechanistic pathway (APP-TNFRSF21 necroptosis), single lab\",\n      \"pmids\": [\"39702278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FOLR2+ macrophages in gastric cancer suppress CD8+ T cell function by expressing PD-L1 and secreting IL-10. Disruption of IL-10 sensitizes anti-PD-1 blockade and promotes antitumor immunity in FOLR2+ TAM-high tumors, demonstrated in fresh tumor tissue culture.\",\n      \"method\": \"In vitro culture of fresh tumor tissue, multiplex immunohistochemistry, transcriptional data analysis\",\n      \"journal\": \"International journal of surgery (London, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, ex vivo tumor culture without full mechanistic reconstitution; functional pathway (IL-10-mediated CD8+ T cell suppression) partially established\",\n      \"pmids\": [\"41263393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-622 directly targets FOLR2 mRNA to promote colorectal cancer cell proliferation. FOLR2 was validated as a functional target of miR-622 via dual luciferase assay; FOLR2 negatively correlates with cell cycle gene signatures, and its suppression by miR-622 drives cell cycle progression.\",\n      \"method\": \"Dual luciferase reporter assay, gain-of-function and loss-of-function experiments in vitro and in vivo, bioinformatics\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus in vitro and in vivo functional experiments, single lab\",\n      \"pmids\": [\"38166756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CLL cells acquire functional FOLR2 protein from nurse-like cells (NLCs) via trogocytosis, enhancing their folate uptake. FOLR2+ CLL cells (those that acquired FOLR2 by trogocytosis) are the predominant actively cycling cancer cell population. This was confirmed by multiplex immunofluorescence in CLL patient lymph nodes.\",\n      \"method\": \"Primary patient cell coculture, flow cytometry, multiplex immunofluorescence of lymph node biopsies, proliferation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, trogocytosis mechanism inferred from correlative and coculture data without direct mechanistic reconstitution\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FOLR2-encoded folate receptor beta (FRβ) was predicted and experimentally validated to bind PFNA, PFOA, and PFOS (but not PFHxS, PFBS, or GenX) by in vitro protein binding analysis, correlating with their in vivo neurodevelopmental toxicity in zebrafish.\",\n      \"method\": \"Reverse molecular docking (computational), in vitro protein binding assay, in vivo zebrafish loss-of-function and rescue experiments\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab; in vitro binding validated but mechanistic link between FRβ binding and neurotoxicity is inferential; zebrafish ortholog used\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In aging mouse testes, FOLR2+ resident macrophages undergo a phenotypic transition toward a pro-inflammatory state driven by mitochondrial metabolic dysfunction, specifically inhibition of IDH2 (a TCA cycle enzyme). This transition facilitates recruitment of monocytes and CD8+ T cells via the CCL8-CCR2/CCR5 axis.\",\n      \"method\": \"Single-cell RNA sequencing, multiplex immunofluorescence, IDH2 inhibition experiments\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, IDH2 inhibition mechanistic link is pharmacological without genetic reconstitution; CCL8-CCR2/CCR5 axis inferred from transcriptomics\",\n      \"pmids\": [\"41618065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOLR2 encodes folate receptor beta (FRβ), a GPI-anchored folate-binding protein expressed predominantly on tissue-resident macrophages, where its transcription is driven by the PU.1 transcription factor; FOLR2+ macrophages localize in perivascular stromal areas and interact with CD8+ T cells via antigen cross-presentation and the CXCL9-CXCR3 axis to promote antitumor immunity, while in some contexts they can suppress T cell function through PD-L1 and IL-10; their differentiation in skin requires STAT6/ALK5-dependent intrinsic signals for FRβ expression and fibroblast-derived laminin/collagen signals (via SHP1/STAT5) for CD163 co-expression; in CKD, FOLR2+ macrophages promote myofibroblast differentiation through WNT/β-catenin signaling; and the protein functions as a bona fide folate uptake receptor that can be transferred between cells by trogocytosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOLR2 encodes folate receptor beta (FRβ), a folate-binding protein that functions as a folate uptake receptor and serves as a defining marker of tissue-resident macrophages, in which it is expressed on mature myeloid cells but not on CD34+ hematopoietic stem cells [#2, #11]. Its transcription in myeloid cells is driven by the PU.1 transcription factor acting through a cluster of PU.1-binding elements upstream of the first exon [#0], and during M-CSF-driven macrophage differentiation in skin FRβ expression depends on intrinsic STAT6/ALK5 signaling, with co-expressed markers such as CD163 instead requiring fibroblast-derived laminin/collagen cues via an SHP1/STAT5 pathway [#3]. FOLR2+ macrophages occupy perivascular tumor stroma where they prime and activate CD8+ T cell cytotoxicity through antigen cross-presentation and the CXCL9-CXCR3 axis, supporting antitumor immunity [#1, #6, #7]. In other contexts these macrophages drive tissue remodeling, promoting myofibroblast differentiation in chronic kidney disease through WNT/β-catenin signaling [#4]. The folate-binding protein itself can be transferred between cells, with malignant cells acquiring functional FRβ by trogocytosis to enhance folate uptake [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing where FRβ protein is and is not expressed defined its value as a lineage-restricted target, distinguishing mature myeloid cells from hematopoietic progenitors.\",\n      \"evidence\": \"Flow cytometry with a high-affinity FRβ antibody plus CAR T cytotoxicity and HSC colony assays in vitro and in xenografts\",\n      \"pmids\": [\"26898190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address folate-binding function of FRβ\", \"Expression pattern in non-myeloid tissues not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A knockdown screen in a lung cancer line linked FOLR2 to PI3K/AKT/mTOR signaling and proliferation, raising a possible cell-intrinsic oncogenic role.\",\n      \"evidence\": \"siRNA knockdown with Western blot, viability, cell cycle and apoptosis readouts in NCI-H1650 cells\",\n      \"pmids\": [\"30415267\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No rescue or reconstitution experiment\", \"NSCLC cell line context may not reflect canonical FRβ macrophage biology\", \"Mechanism connecting FRβ to AKT/mTOR unestablished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying PU.1 as the transcriptional driver explained why FOLR2 is restricted to the myeloid lineage.\",\n      \"evidence\": \"siRNA knockdown of PU.1 plus luciferase reporter analysis of the FOLR2 proximal regulatory region\",\n      \"pmids\": [\"32532019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other co-regulators of macrophage-specific expression not defined\", \"Does not address signal-dependent tuning of expression\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Localizing FOLR2+ macrophages to perivascular tumor stroma and showing they prime CD8+ T cells reframed FRβ+ macrophages as immunostimulatory players in the tumor microenvironment.\",\n      \"evidence\": \"Immunofluorescence localization and ex vivo CD8+ T cell priming coculture in breast cancer\",\n      \"pmids\": [\"35325594\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of priming not resolved here\", \"Causal contribution to tumor control in vivo not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Dissecting FRβ versus CD163 induction during macrophage differentiation separated cell-intrinsic from microenvironmental control of the FRβ+ macrophage phenotype.\",\n      \"evidence\": \"scRNA-seq, fibroblast coculture, and pharmacological inhibition of STAT6/ALK5/SHP1 in skin macrophages\",\n      \"pmids\": [\"39720957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT6/ALK5 binding at the FOLR2 locus not shown\", \"Generalizability beyond skin macrophages untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing FOLR2+ macrophages drive fibroblast-to-myofibroblast conversion via WNT/β-catenin identified a pro-fibrotic, tissue-remodeling role distinct from their immune functions.\",\n      \"evidence\": \"Macrophage-fibroblast coculture, WNT/β-catenin pathway analysis, scRNA-seq and multiplex IHC in chronic kidney disease\",\n      \"pmids\": [\"38272907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WNT ligand source and identity not defined\", \"In vivo genetic depletion not performed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying FOLR2 as a direct miR-622 target connected its loss to cell cycle progression in colorectal cancer.\",\n      \"evidence\": \"Dual luciferase target validation with gain- and loss-of-function experiments in vitro and in vivo\",\n      \"pmids\": [\"38166756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether FRβ acts cell-intrinsically in tumor cells or via macrophages unclear\", \"Mechanism of cell cycle suppression by FRβ not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating antigen cross-presentation by FOLR2+ macrophages and their epithelial-driven necroptosis tied their abundance to gastric cancer progression.\",\n      \"evidence\": \"scRNA-seq, multiplex IHC, FOLR2+/FOLR2- macrophage-CD8+ T cell cocultures in gastric cancer\",\n      \"pmids\": [\"39702278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"APP-TNFRSF21 necroptosis axis correlative\", \"Antigen specificity of cross-presentation not characterized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining the CXCL9-CXCR3 axis provided the molecular mechanism by which FOLR2+ macrophages activate CD8+ T cell cytotoxicity and mediate antitumor effects.\",\n      \"evidence\": \"scRNA-seq, bulk RNA-seq, coculture, and in vivo mouse experiments in breast cancer\",\n      \"pmids\": [\"40045365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals inducing CXCL9 secretion not resolved\", \"Reconciliation with immunosuppressive contexts not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing FOLR2+ macrophages can also suppress CD8+ T cells via PD-L1 and IL-10 revealed context-dependent, opposing immune functions.\",\n      \"evidence\": \"Ex vivo fresh tumor tissue culture, multiplex IHC and transcriptional analysis in gastric cancer\",\n      \"pmids\": [\"41263393\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full mechanistic reconstitution of IL-10/PD-L1 suppression\", \"Conflicts with stimulatory roles reported elsewhere remain unreconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Trogocytic transfer of functional FRβ from nurse-like cells to CLL cells linked the receptor's folate-uptake function to cancer cell proliferation.\",\n      \"evidence\": \"Primary patient cell coculture, flow cytometry, and multiplex immunofluorescence of CLL lymph nodes (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Trogocytosis mechanism inferred from correlative coculture data\", \"Preprint, not independently confirmed\", \"Direct demonstration of folate flux through transferred receptor incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linking IDH2-driven mitochondrial dysfunction to a pro-inflammatory shift in testicular FOLR2+ macrophages connected metabolic state to their phenotypic plasticity in aging.\",\n      \"evidence\": \"scRNA-seq, multiplex immunofluorescence, and pharmacological IDH2 inhibition in aging mouse testes\",\n      \"pmids\": [\"41618065\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"IDH2 link is pharmacological without genetic reconstitution\", \"CCL8-CCR2/CCR5 recruitment axis inferred from transcriptomics\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FRβ's folate-binding biochemistry mechanistically governs the divergent immunostimulatory versus immunosuppressive and pro-fibrotic behaviors of FOLR2+ macrophages remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of FRβ ligand binding in the corpus\", \"Context determinants of stimulatory vs suppressive macrophage states undefined\", \"Whether folate uptake itself drives macrophage phenotype is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":4,"faith_pct":50.0}}