{"gene":"CD276","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2023,"finding":"mTORC1 upregulates B7-H3 (CD276) expression via direct phosphorylation of the transcription factor YY2 by p70 S6 kinase (S6K). B7-H3 deficiency in mTORC1-hyperactive tumors suppresses tumor growth through an immune-mediated mechanism involving increased T-cell activity, IFN-γ responses, and increased tumor cell MHC-II expression, with strikingly increased cytotoxic CD38+CD39+CD4+ T cells.","method":"Mechanistic experiments including phosphorylation assays, transcription factor identification, genetic KO models, CITE-seq, and in vivo tumor studies","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct phosphorylation mechanism identified, multiple orthogonal methods (CITE-seq, KO models, in vivo), single lab but rigorous mechanistic follow-up","pmids":["36869048"],"is_preprint":false},{"year":2023,"finding":"FUT8 mediates core fucosylation of CD276 (B7-H3) at N104. FUT8-silence-induced defucosylation at N104 on B7-H3 causes HSC70 (HSPA8) to bind the 106-110 SLRLQ motif of B7-H3, propelling lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway via HSC70/LAMP2A.","method":"Mutagenesis, co-immunoprecipitation, lysosomal degradation assays, small-molecule inhibitor (FDW028), in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — specific N104 fucosylation site identified by mutagenesis, binding partner (HSC70) and degradation pathway (CMA/LAMP2A) established with orthogonal methods in single lab","pmids":["37537172"],"is_preprint":false},{"year":2025,"finding":"Lactate-upregulated histone H3K18 lactylation (H3K18la) directly binds to the B7-H3 promoter in conjunction with transcription factor Creb1 and co-activator Ep300, leading to increased B7-H3 expression and tumor immune evasion by reducing CD8+ T cell cytotoxicity.","method":"ChIP assay, LDHA knockdown, pharmacological glycolysis inhibition, in vivo tumor models, CD8+ T cell functional assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — ChIP identifies Creb1/Ep300 at B7-H3 promoter, mechanism validated with orthogonal inhibition approaches, single lab","pmids":["39990209"],"is_preprint":false},{"year":2019,"finding":"B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by upregulating hexokinase 2 (HK2) expression. Depletion of HK2 or treatment with HK2 inhibitors reverses B7-H3-induced glycolysis and chemoresistance.","method":"B7-H3 overexpression/knockdown, glucose consumption and lactate production assays, HK2 siRNA and inhibitor experiments, in vitro functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined metabolic phenotype, HK2 identified as downstream effector with epistasis via siRNA and inhibitors, single lab","pmids":["30952834"],"is_preprint":false},{"year":2020,"finding":"B7-H3 promotes colorectal cancer angiogenesis by activating the NF-κB pathway to upregulate VEGFA expression. Conditioned medium from B7-H3 knockdown CRC cells inhibited HUVEC migration, invasion, and tube formation; recombinant VEGFA rescued this effect, and VEGFA siRNA or neutralizing antibody reversed B7-H3 overexpression effects.","method":"B7-H3 knockdown/overexpression, conditioned medium experiments on HUVECs, VEGFA siRNA and neutralizing antibody, NF-κB pathway inhibition, in vivo experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established via NF-κB/VEGFA axis with multiple rescue experiments, single lab","pmids":["31974361"],"is_preprint":false},{"year":2021,"finding":"B7-H3 (Cd276) knockout in tumor cells (but not stromal cells) suppresses ovarian cancer progression and reduces M2 macrophage number while increasing IFNγ+CD8+ T cells. B7-H3 expression drives immunosuppression via the CCL2-CCR2-M2 macrophage axis; CCL2 was downregulated in B7-H3 KO tumor cells, and inhibition of CCL2-CCR2 partly negated B7-H3 suppression effects on M2 macrophage migration/differentiation.","method":"Syngeneic mouse KO models (tumor cell-specific Cd276 KO), flow cytometry, transcriptome analysis, CCL2-CCR2 axis inhibition experiments","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tumor-cell-specific KO with defined immune phenotype, CCL2 mechanistic link established with multiple orthogonal methods, single lab","pmids":["34799346"],"is_preprint":false},{"year":2023,"finding":"Loss of PTEN and TP53 induces B7-H3 expression by activating transcription factor Sp1. Prostate-specific deletion of Cd276 in Pten/Trp53 genetically engineered mouse models delayed tumor progression and reversed suppression of tumor-infiltrating T cells and NK cells.","method":"Genetically engineered mouse models (GEMM), Sp1 transcription factor experiments, in vivo prostate-specific Cd276 deletion, immune cell phenotyping","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — PTEN/TP53-Sp1-B7-H3 transcriptional axis established in GEMM with prostate-specific KO and immune phenotyping, single lab with multiple methods","pmids":["37163614"],"is_preprint":false},{"year":2017,"finding":"B7-H3 promotes gastric cancer cell migration and invasion through interaction with CXCR4. B7-H3 silencing downregulated CXCR4 and inhibited AKT, ERK, and Jak2/Stat3 phosphorylation. Co-immunoprecipitation assays demonstrated a direct protein-protein interaction between B7-H3 and CXCR4, and immunofluorescence confirmed co-localization.","method":"shRNA-mediated B7-H3 silencing, co-immunoprecipitation, immunofluorescence co-localization, in vitro migration/invasion assays, in vivo metastasis model (tail vein injection)","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP establishes B7-H3/CXCR4 interaction, downstream signaling changes confirmed, in vivo validation, single lab","pmids":["29069741"],"is_preprint":false},{"year":2022,"finding":"B7-H3 (CD276) is highly expressed in mouse and human adipose tissue, particularly in adipocyte progenitor cells, and is rapidly downregulated upon initiation of adipocyte differentiation. Loss of B7-H3 in progenitors results in impaired oxidative metabolism and increased lipid accumulation. B7-H3 knockout mice develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation.","method":"RNA sequencing, metabolic studies, B7-H3 KO mouse model, adipocyte differentiation assays, mitochondrial activity measurements","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse model with clear metabolic phenotype, RNA-seq and metabolic assays orthogonally support B7-H3 role in adipocyte progenitor metabolism, single lab","pmids":["35476450"],"is_preprint":false},{"year":2020,"finding":"B7-H3 regulates KIF15 expression (independent of NF-κB pathway, as revealed by RNA sequencing), and the B7-H3/KIF15 axis activates ERK1/2 signaling to confer radioresistance in colorectal cancer. siRNA-mediated KIF15 silencing or KIF15 inhibitor SB743921 abolished B7-H3-mediated radioresistance in vitro and in vivo.","method":"RNA sequencing, siRNA knockdown, specific KIF15 inhibitor (SB743921), B7-H3 blocking antibody (3E8) in vivo, colony formation assays, cell cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq identifies KIF15, epistasis confirmed via siRNA and pharmacological inhibitor, in vivo validation included, single lab","pmids":["33011740"],"is_preprint":false},{"year":2016,"finding":"B7-H3 increases thymidylate synthase (TS) expression via activation of the PI3K/Akt pathway, resulting in colorectal cancer cell resistance to 5-fluorouracil. The PI3K-specific inhibitor LY294002 blocked B7-H3-induced PI3K/Akt activation and TS upregulation.","method":"B7-H3 overexpression in SW480 and HCT8 cells, CCK-8 cell viability assays, Western blotting for TS and PI3K/Akt, pharmacological inhibition with LY294002","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibition places B7-H3 upstream of PI3K/Akt/TS, multiple cell lines, single lab","pmids":["26787540"],"is_preprint":false},{"year":2019,"finding":"B7-H3 expression in pancreatic cancer is regulated at the transcriptional level by BRD4 (a BET bromodomain protein). BET inhibitors decreased B7-H3 protein and mRNA levels. Furthermore, the BRD4/B7-H3 axis modulates TLR4 expression in pancreatic cancer cells.","method":"BET inhibitor drug screening, BRD4 knockdown, RT-PCR and Western blotting for B7-H3 and TLR4, pancreatic cancer cell line experiments","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — BRD4 identified as transcriptional regulator of B7-H3 with pharmacological and siRNA evidence, downstream TLR4 pathway identified, single lab","pmids":["30664982"],"is_preprint":false},{"year":2016,"finding":"B7-H3 upregulates BRCC3 (a component of the BRCA1-BRCA2-BRCC3 DNA repair complex) expression, enhancing DNA repair and conferring resistance to 5-fluorouracil-induced DNA damage in colorectal cancer. BRCC3 knockdown in B7-H3-overexpressing cells permitted greater 5-Fu-induced DNA damage.","method":"mRNA microarray, RT-PCR, Western blotting, DNA comet assay for DNA damage, siRNA knockdown of BRCC3 in B7-H3 overexpressing cells","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established via BRCC3 knockdown in B7-H3 overexpressing cells using DNA damage readout, multiple methods, single lab","pmids":["27175567"],"is_preprint":false},{"year":2018,"finding":"CD276 (B7-H3) knockdown in late endothelial progenitor cells (LEPCs) significantly decreased proliferation and migration while increasing apoptosis. CD276 knockdown caused cell cycle arrest at G0/G1, increased cyclin D2/D3/E1-CDK2/4/6, decreased cyclin A/B-CDK1, decreased pErk1/2 and pAkt. Paradoxically, CD276 KD increased tube formation and angiogenesis in vitro and in vivo, with upregulation of FoxC1/C2 and Hey1/2 (Notch arterial differentiation pathway) and VEGF-VEGFR1 and p-p38.","method":"Lentiviral knockdown, FACS cell cycle analysis, tube formation assay in vitro, Matrigel plug angiogenesis assay in vivo, Western blotting for signaling molecules","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lentiviral KD with multiple orthogonal readouts (proliferation, migration, angiogenesis, signaling), in vitro and in vivo confirmation, single lab","pmids":["30379377"],"is_preprint":false},{"year":2021,"finding":"B7-H3 regulates osteoclast differentiation as a positive physiologic regulator. B7-H3 deficiency inhibits osteoclastogenesis in human osteoclast precursors (OCPs). Mechanistically, B7-H3 inhibition upregulates type-I IFN signaling and IFN-inducible IDO expression; pharmacological inhibition of type-I IFN or IDO knockdown reverses B7-H3-deficiency-mediated osteoclastogenesis suppression.","method":"High-throughput transcriptomics, pharmacological inhibition of type-I IFN, IDO knockdown, osteoclast differentiation assays in human OCPs","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomics identifies IFN-IDO axis, pharmacological and siRNA epistasis confirms pathway positioning, single lab","pmids":["34671026"],"is_preprint":false},{"year":2011,"finding":"Stimulation of surface B7-H3 on human marrow stromal cells (hMSCs) with a specific anti-B7-H3 monoclonal antibody (4H7) promotes osteoblast differentiation, increasing alkaline phosphatase and osteocalcin markers and mineralized nodule formation. B7-H3 stimulation also increased OPG expression and decreased RANKL expression. This effect was abolished by addition of B7-H3-Fc fusion protein, confirming membrane B7-H3 specificity.","method":"Anti-B7-H3 mAb stimulation, B7-H3-Fc competitive blocking, osteoblast differentiation assays (ALP, osteocalcin, mineralized nodule quantification), Western blotting for OPG/RANKL","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody stimulation and Fc competitive blocking establish B7-H3 membrane function, multiple differentiation markers measured, single lab","pmids":["21893365"],"is_preprint":false},{"year":2020,"finding":"SRSF3 splicing factor directly binds to B7-H3 mRNA and contributes to the retention of B7-H3 exon 4, thereby regulating B7-H3 expression in colorectal cancer. RNA immunoprecipitation (RIP) confirmed direct SRSF3-B7-H3 mRNA binding. Knockdown of SRSF3 reduced B7-H3 mRNA and protein, while SRSF3 overexpression increased B7-H3 expression.","method":"Individual knockdown of splicing factors, RNA immunoprecipitation (RIP), minigene construct with B7-H3 exons 3-6, qPCR and Western blotting","journal":"Cancer immunology, immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding established by RIP, minigene exon retention confirmed, multiple orthogonal methods, single lab","pmids":["32719950"],"is_preprint":false},{"year":2023,"finding":"EBV infection induces B7-H3 expression in nasopharyngeal carcinoma (NPC) via activation of the PI3K/AKT/mTOR signaling pathway through EBV latent membrane protein 1 (LMP1). B7-H3 expression on EBV+ NPC tumor cells negatively correlates with and inhibits NK cell cytotoxic function in vitro and in vivo.","method":"EBV infection models, LMP1 expression constructs, PI3K/AKT/mTOR inhibitor experiments, NK cell cytotoxicity assays, NPC xenograft mouse model with adoptive NK cell transfer","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LMP1-PI3K/AKT/mTOR mechanism established with pathway inhibitors, in vitro and in vivo NK functional assays confirm B7-H3 immunosuppressive role, single lab","pmids":["36996321"],"is_preprint":false},{"year":2023,"finding":"CRC-derived exosomal B7-H3 is taken up by human umbilical vein endothelial cells (HUVECs) and activates the AKT1/mTOR/VEGFA signaling pathway, enhancing HUVEC migration, invasion, and tube formation, and promoting pulmonary angiogenesis and CRC metastasis in mice.","method":"Exosome isolation and uptake assays, AKT1/mTOR/VEGFA pathway analysis, HUVEC functional assays (migration, invasion, tube formation), in vivo CRC metastasis mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosomal B7-H3 uptake demonstrated, AKT1/mTOR/VEGFA pathway activation confirmed, in vivo validation, single lab","pmids":["37263461"],"is_preprint":false},{"year":2022,"finding":"B7-H3 promotes EMT in NSCLC by upregulating SIRT1 expression via the PI3K/AKT pathway. CRISPR/Cas9-mediated B7-H3 deletion downregulated SIRT1 and phosphorylated AKT in A549 cells, resulting in increased E-cadherin and decreased N-cadherin and vimentin. PI3K inhibitor LY294002 suppressed SIRT1 expression, placing B7-H3 upstream of PI3K/AKT/SIRT1 in this EMT pathway.","method":"CRISPR/Cas9 B7-H3 deletion, SIRT1 siRNA, PI3K inhibitor LY294002, Western blotting for EMT markers and signaling molecules, migration and invasion assays","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO and SIRT1 siRNA epistasis, pharmacological PI3K inhibition places B7-H3 in pathway, single lab","pmids":["35029291"],"is_preprint":false},{"year":2021,"finding":"B7-H3 inhibits apoptosis in gastric cancer cells through an FN (fibronectin)-dependent pathway. B7-H3 interacts with fibronectin and subsequently activates PI3K/AKT signaling, suppressing pro-apoptotic proteins (Caspase 3, 8, 9, Bax, p53, Apaf-1, Cleaved PARP) and upregulating Bcl-2.","method":"shRNA B7-H3 knockdown, bioinformatics correlation (TCGA), co-immunoprecipitation of B7-H3 and fibronectin, apoptosis protein expression by Western blot, exogenous FN rescue experiments","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP establishes B7-H3/FN interaction, multiple apoptosis markers measured, exogenous FN rescue confirms pathway dependence, single lab","pmids":["35003371"],"is_preprint":false},{"year":2021,"finding":"Fibronectin (FN) interacts with B7-H3 in clear cell renal cell carcinoma and promotes tumor metastasis by activating PI3K, AKT, p38, and ERK kinases. B7-H3 knockdown abolished the pro-metastatic effect of exogenous FN, establishing B7-H3 as a required mediator of FN-induced metastasis signaling.","method":"B7-H3 knockdown, exogenous FN treatment, co-immunoprecipitation/database correlation for B7-H3-FN interaction, migration/invasion assays, Western blotting for PI3K/AKT/p38/ERK","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — FN interaction confirmed, epistasis established by B7-H3 KD abolishing FN effects, single lab","pmids":["34431237"],"is_preprint":false},{"year":2023,"finding":"B7-H3 promotes cancer stem cell characteristics in gastric cancer through activation of the AKT/Nrf2/glutathione (GSH) metabolism pathway. B7-H3 knockdown suppressed stemness markers and GSH metabolism; inhibition of AKT signaling suppressed both GSH metabolism and GC stemness. Mass spectrometry identified downregulation of GSH metabolism in shB7-H3 cells.","method":"shRNA B7-H3 knockdown, B7-H3 overexpression, mass spectrometry metabolic profiling, Western blotting for AKT/Nrf2, sphere formation assays, multi-color IHC on human tissues, in vivo xenograft","journal":"Chinese medical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identifies GSH pathway, AKT/Nrf2 mechanistic axis confirmed, multiple methods including in vivo, single lab","pmids":["37488673"],"is_preprint":false},{"year":2019,"finding":"B7-H3 promotes angiogenesis in endothelial cells (HUVECs) through enhancement of VEGF secretion. B7-H3 knockdown decreased HUVEC proliferation, migration, tube formation, and VEGF expression in vitro, and impaired functional vascular network formation in Matrigel plug assays in vivo.","method":"B7-H3 transient knockdown in HUVECs, VEGF ELISA, proliferation/migration/tube formation assays, in vivo Matrigel plug assay","journal":"Immunologic research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — KD with defined angiogenic phenotype and VEGF secretion as mechanism, in vitro and in vivo confirmed, single lab","pmids":["31292886"],"is_preprint":false},{"year":2024,"finding":"B7-H3 expression in CRPC is negatively regulated by androgen receptor (AR) during the early phase of ADT treatment, but is positively associated with PCa proliferation during subsequent disease progression. These findings were established using patient-derived xenograft (PDX) models longitudinally assessed during post-ADT progression and validated in clinical patient samples.","method":"Longitudinal study using PCa patient-derived xenograft (PDX) models with ADT treatment, immunohistochemistry on clinical patient samples","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — AR regulation of B7-H3 established in PDX models with longitudinal design and clinical validation, single lab","pmids":["37452083"],"is_preprint":false},{"year":2023,"finding":"DNA methylation of the B7-H3 promoter negatively regulates its expression; DNMT inhibition (decitabine) increased B7-H3 expression via demethylation of the B7-H3 locus. This was demonstrated in neuroendocrine prostate cancer and RB1-deficient CRPC models.","method":"DNMT gene deletion, decitabine treatment, B7-H3 expression analysis in patient-derived xenograft models, methylation analysis","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNMT deletion and pharmacological inhibition both increase B7-H3 via demethylation, tested in multiple models, single lab","pmids":["37967200"],"is_preprint":false},{"year":2018,"finding":"B7-H3 expressed on tumor cells suppresses CD8+ T-cell-mediated immune surveillance. Anti-B7-H3 blockade in a syngeneic murine cancer model increased CD8+ TIL numbers and restored effector function; CD8+ T-cell depletion negated this antitumor efficacy. Dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction beyond either agent alone.","method":"Anti-B7-H3 blocking antibody in syngeneic murine model, CD8+ T-cell depletion experiment, flow cytometry for TIL quantification and function, dual antibody blockade experiment","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD8 depletion epistasis establishes mechanistic requirement, syngeneic model with functional immune readouts, single lab","pmids":["29530936"],"is_preprint":false},{"year":2003,"finding":"Mouse B7-H3 mediates antitumor immunity through CD8+ T cells and NK cells (with no contribution from CD4+ T cells). Intratumoral injection of a mouse B7-H3 expression plasmid caused complete regression of 50% of EL-4 lymphoma tumors and generated systemic immunity. CD8+ T cell and NK cell depletion experiments established the cellular requirements for B7-H3-mediated antitumor activity.","method":"Intratumoral plasmid injection in mouse EL-4 lymphoma model, immune cell depletion (CD8+ T cell, NK cell, CD4+ T cell), tumor rechallenge to assess systemic immunity","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immune cell depletion epistasis identifies required effector cells, tumor rechallenge confirms systemic immunity, single lab in vivo","pmids":["12939639"],"is_preprint":false},{"year":2021,"finding":"GM-CSF, enriched in gastric cancer tumor tissue, induces B7-H3 expression on neutrophils via JAK-STAT3 signaling pathway activation, in both time-dependent and dose-dependent manners.","method":"Tumor culture supernatant experiments, GM-CSF dose-response and time-course experiments on neutrophils, JAK-STAT3 pathway inhibition, flow cytometry","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — dose-dependent GM-CSF induction of B7-H3 via JAK-STAT3 confirmed with pharmacological inhibition, single lab","pmids":["33945871"],"is_preprint":false},{"year":2019,"finding":"B7-H3 confers β-catenin-dependent co-localization; β-catenin co-localizes with B7-H3 and promotes its expression in adamantinomatous craniopharyngiomas, as shown by immunofluorescence and Western blot analysis.","method":"Immunofluorescence co-localization, Western blot analysis, immunohistochemistry on 44 craniopharyngioma samples","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization by IF only, no direct interaction assay or mechanistic epistasis confirmed, single lab","pmids":["31043272"],"is_preprint":false},{"year":2024,"finding":"CAR T cells based on camel nanobodies recognizing the IgC domain (but not the IgV domain) of B7-H3 had more potent antitumor activity than IgV-targeting nanobody CAR-T cells. Single-cell RNA sequencing and T-cell proteomics identified top upregulated genes critical for polyfunctional CAR-T cell persistence, establishing the IgC epitope as optimal for CAR activation.","method":"Camel nanobody generation targeting IgC vs IgV epitopes, CAR-T cell construction, in vivo antitumor efficacy in mice, single-cell RNA sequencing, T-cell proteomics","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitope domain comparison with scRNA-seq and proteomics, in vivo validation, single lab with multiple orthogonal methods","pmids":["37739951"],"is_preprint":false}],"current_model":"CD276 (B7-H3) is a type I transmembrane glycoprotein of the B7 immune checkpoint family whose expression is transcriptionally regulated by Sp1 (downstream of PTEN/TP53 loss), BRD4, SRSF3-mediated mRNA splicing, promoter methylation/demethylation, mTORC1-driven YY2 phosphorylation by S6K, and lactate-induced H3K18 lactylation recruiting Creb1/Ep300 to its promoter; at the protein level, FUT8-mediated core fucosylation at N104 stabilizes B7-H3 by preventing HSC70/LAMP2A-mediated chaperone-mediated autophagy degradation. B7-H3 suppresses antitumor immunity by inhibiting CD8+ T cell and NK cell activity, driving M2 macrophage polarization via the CCL2-CCR2 axis, and its deletion in tumors relieves immunosuppression and slows cancer progression. Non-immunologically, B7-H3 promotes glycolysis via HK2, drug resistance via BRCC3-mediated DNA repair, radioresistance via KIF15/ERK1/2, EMT via PI3K/AKT/SIRT1, angiogenesis via NF-κB/VEGFA and VEGF secretion from endothelial cells, metastasis by interacting with CXCR4 and fibronectin to activate PI3K/AKT, and cancer stemness via AKT/Nrf2/GSH metabolism; it also regulates osteoblast differentiation and positively controls osteoclastogenesis through suppression of type-I IFN/IDO signaling, and in adipose progenitors it sustains oxidative metabolism such that B7-H3 KO mice develop spontaneous obesity."},"narrative":{"mechanistic_narrative":"CD276 (B7-H3) is a cell-surface immune checkpoint molecule that suppresses antitumor immunity while concurrently driving tumor-intrinsic programs of metabolism, survival, and metastasis [PMID:29530936, PMID:12939639]. Tumor-cell B7-H3 restrains CD8+ T-cell and NK-cell effector function: antibody blockade increases tumor-infiltrating CD8+ T cells and restores their cytotoxicity, an effect lost upon CD8+ T-cell depletion and enhanced by dual PD-L1 blockade [PMID:29530936], and its forced expression in mouse tumors mediates regression dependent on both CD8+ T cells and NK cells [PMID:12939639]. B7-H3 also reshapes the myeloid compartment, promoting M2 macrophage recruitment and differentiation through tumor-cell CCL2 acting on the CCL2-CCR2 axis [PMID:34799346], and inhibits NK cytotoxicity in EBV-driven nasopharyngeal carcinoma [PMID:36996321]. Its expression is tightly controlled at multiple levels: transcriptionally by Sp1 downstream of PTEN/TP53 loss [PMID:37163614], by BRD4 [PMID:30664982], by androgen receptor in prostate cancer [PMID:37452083], by promoter DNA methylation reversed by DNMT inhibition [PMID:37967200], and by lactate-driven H3K18 lactylation recruiting Creb1/Ep300 to its promoter [PMID:39990209]; by mTORC1 via S6K-mediated phosphorylation of YY2 [PMID:36869048]; post-transcriptionally by SRSF3-dependent exon 4 retention [PMID:32719950]; and post-translationally by FUT8-mediated core fucosylation at N104, which prevents HSC70/LAMP2A-mediated chaperone-mediated autophagy degradation [PMID:37537172]. Independent of immune modulation, B7-H3 acts as a tumor-cell signaling hub that engages partners including CXCR4 and fibronectin to activate PI3K/AKT signaling driving migration, invasion, EMT, apoptosis resistance, and stemness [PMID:29069741, PMID:35003371, PMID:34431237, PMID:37488673], promotes aerobic glycolysis via HK2 [PMID:30952834], confers chemo- and radioresistance via BRCC3-mediated DNA repair and a KIF15/ERK1/2 axis [PMID:27175567, PMID:33011740], and stimulates angiogenesis through NF-κB/VEGFA and VEGF secretion [PMID:31974361, PMID:31292886]. Beyond cancer, B7-H3 is a physiologic regulator of bone and metabolism: it promotes osteoblast differentiation and positively controls osteoclastogenesis by suppressing type-I IFN/IDO signaling [PMID:21893365, PMID:34671026], and sustains oxidative metabolism in adipocyte progenitors such that its loss produces spontaneous obesity in mice [PMID:35476450].","teleology":[{"year":2003,"claim":"Established which immune effectors mediate B7-H3-dependent antitumor activity, defining its immunological function before downstream mechanisms were known.","evidence":"Intratumoral B7-H3 plasmid injection with CD8+ T-cell, NK-cell, and CD4+ T-cell depletion in mouse EL-4 lymphoma","pmids":["12939639"],"confidence":"Medium","gaps":["Plasmid overexpression context; relationship to endogenous tumor B7-H3 immunosuppression unresolved","Receptor on T/NK cells not identified","Costimulatory vs coinhibitory role context-dependent"]},{"year":2011,"claim":"Showed B7-H3 has a non-immune physiologic role by demonstrating membrane B7-H3 stimulation drives osteoblast differentiation and shifts OPG/RANKL balance.","evidence":"Anti-B7-H3 mAb stimulation with B7-H3-Fc competitive blocking in human marrow stromal cells","pmids":["21893365"],"confidence":"Medium","gaps":["Counter-receptor for membrane B7-H3 unknown","Intracellular signaling pathway not defined","Antibody agonism may not mimic physiologic ligand"]},{"year":2016,"claim":"Identified tumor-intrinsic, immune-independent mechanisms of chemoresistance, recasting B7-H3 as a signaling effector inside tumor cells.","evidence":"B7-H3 overexpression/knockdown with PI3K/Akt inhibition (LY294002), BRCC3 siRNA, and DNA comet assays in colorectal cancer cells","pmids":["26787540","27175567"],"confidence":"Medium","gaps":["How surface B7-H3 transduces intracellular PI3K/AKT signal unclear","No structural basis for signaling","Single lineage (CRC)"]},{"year":2017,"claim":"Demonstrated a direct physical partner (CXCR4) linking B7-H3 to pro-metastatic kinase signaling.","evidence":"Co-immunoprecipitation, immunofluorescence co-localization, and shRNA knockdown with migration/metastasis assays in gastric cancer","pmids":["29069741"],"confidence":"Medium","gaps":["No reciprocal Co-IP or domain mapping","Direct vs complex-mediated interaction unconfirmed","Stoichiometry unknown"]},{"year":2018,"claim":"Defined endogenous tumor B7-H3 as a CD8+ T-cell checkpoint amenable to combination blockade, anchoring its therapeutic rationale.","evidence":"Anti-B7-H3 blocking antibody with CD8+ depletion and PD-L1 co-blockade in a syngeneic murine model","pmids":["29530936"],"confidence":"Medium","gaps":["T-cell receptor for B7-H3 not identified","Single model","Molecular signal delivered to T cells unknown"]},{"year":2019,"claim":"Expanded the tumor-intrinsic repertoire to metabolic reprogramming and angiogenesis, and identified BRD4 as a transcriptional driver.","evidence":"Knockdown/overexpression with HK2 inhibition, NF-κB inhibition and VEGFA rescue, VEGF ELISA, and BET inhibitor/BRD4 knockdown across CRC and pancreatic models","pmids":["30952834","31974361","31292886","30664982"],"confidence":"Medium","gaps":["Whether glycolytic, angiogenic and transcriptional axes are mechanistically linked unresolved","Effects largely correlative across separate single-lab studies"]},{"year":2020,"claim":"Established post-transcriptional control of B7-H3 by SRSF3 and a radioresistance pathway via KIF15/ERK1/2.","evidence":"RNA immunoprecipitation and minigene exon-retention assays for SRSF3; RNA-seq, KIF15 siRNA/inhibitor SB743921 with in vivo radiation in CRC","pmids":["32719950","33011740"],"confidence":"Medium","gaps":["Functional consequence of exon 4 retention on protein not detailed","How B7-H3 regulates KIF15 transcription unknown"]},{"year":2021,"claim":"Resolved the myeloid arm of immunosuppression (CCL2-CCR2-M2) and demonstrated fibronectin as a B7-H3 partner driving PI3K/AKT survival and metastasis signaling.","evidence":"Tumor-cell-specific Cd276 KO with CCL2-CCR2 inhibition in ovarian cancer; Co-IP of B7-H3 with fibronectin and exogenous-FN rescue in gastric and renal carcinoma","pmids":["34799346","35003371","34431237"],"confidence":"Medium","gaps":["Direct binding interface for fibronectin not mapped","CCL2 regulation mechanism downstream of B7-H3 not detailed"]},{"year":2021,"claim":"Extended physiologic roles to bone homeostasis, showing B7-H3 positively controls osteoclastogenesis through suppression of type-I IFN/IDO.","evidence":"Transcriptomics with type-I IFN inhibition and IDO knockdown in human osteoclast precursors","pmids":["34671026"],"confidence":"Medium","gaps":["Mechanism by which B7-H3 suppresses IFN signaling unknown","Reconciliation with osteoblast-promoting role not addressed"]},{"year":2022,"claim":"Revealed an organismal metabolic function in adipose progenitors, demonstrating B7-H3 sustains oxidative metabolism with KO mice developing spontaneous obesity.","evidence":"RNA-seq, mitochondrial/metabolic assays, and B7-H3 KO mouse phenotyping in adipocyte progenitors","pmids":["35476450"],"confidence":"High","gaps":["Molecular effector linking B7-H3 to oxidative metabolism unidentified","Cell-autonomous vs systemic contribution unclear"]},{"year":2023,"claim":"Integrated upstream regulation across transcription (Sp1/PTEN-TP53, methylation), translation/signaling (mTORC1-S6K-YY2), and protein stability (FUT8 fucosylation/CMA), explaining how B7-H3 levels are set.","evidence":"GEMM with Sp1 axis and prostate-specific Cd276 KO; mTORC1/S6K phosphorylation of YY2 with CITE-seq and KO; FUT8 N104 mutagenesis with HSC70 Co-IP and CMA degradation assays; DNMT deletion/decitabine demethylation","pmids":["37163614","36869048","37537172","37967200"],"confidence":"High","gaps":["Crosstalk among these regulatory inputs not integrated","Relative contribution of each in different tumor types unknown"]},{"year":2023,"claim":"Broadened tumor-intrinsic signaling to EMT (PI3K/AKT/SIRT1), stemness (AKT/Nrf2/GSH), and exosome-mediated angiogenesis, and identified viral and AR-dependent expression control.","evidence":"CRISPR KO with LY294002 (EMT); mass spectrometry and AKT/Nrf2 analysis (stemness); exosome uptake and AKT1/mTOR/VEGFA assays; EBV-LMP1/PI3K-AKT-mTOR and PDX/ADT-AR models","pmids":["35029291","37488673","37263461","36996321","37452083"],"confidence":"Medium","gaps":["Convergence of multiple AKT-centric phenotypes onto a single mechanism unresolved","Many readouts single-lineage and correlative"]},{"year":2025,"claim":"Connected metabolic state to B7-H3 transcription via lactate-driven histone lactylation, linking the tumor metabolic environment to immune evasion.","evidence":"ChIP for H3K18la/Creb1/Ep300 at the B7-H3 promoter, LDHA knockdown, glycolysis inhibition, and CD8+ T-cell assays in vivo","pmids":["39990209"],"confidence":"Medium","gaps":["Direct causal chain from lactate to promoter occupancy needs orthogonal confirmation","Single lab"]},{"year":null,"claim":"The bona fide receptor(s) that B7-H3 engages on T and NK cells to deliver its inhibitory signal remains unidentified, leaving the core mechanism of immune checkpoint function undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No counter-receptor identified in the corpus","How a cell-surface checkpoint also acts as an intracellular PI3K/AKT signaling node is unresolved","No structural model of B7-H3 in ligand/receptor complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[26,27,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[7,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[15,26,30]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,27,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,20,21,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,8,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,11,2,25]}],"complexes":[],"partners":["CXCR4","FN1","HSPA8","FUT8","LAMP2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5ZPR3","full_name":"CD276 antigen","aliases":["4Ig-B7-H3","B7 homolog 3","B7-H3","Costimulatory molecule"],"length_aa":534,"mass_kda":57.2,"function":"May participate in the regulation of T-cell-mediated immune response. May play a protective role in tumor cells by inhibiting natural-killer mediated cell lysis as well as a role of marker for detection of neuroblastoma cells. May be involved in the development of acute and chronic transplant rejection and in the regulation of lymphocytic activity at mucosal surfaces. Could also play a key role in providing the placenta and fetus with a suitable immunological environment throughout pregnancy. Both isoform 1 and isoform 2 appear to be redundant in their ability to modulate CD4 T-cell responses. Isoform 2 is shown to enhance the induction of cytotoxic T-cells and selectively stimulates interferon gamma production in the presence of T-cell receptor signaling","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q5ZPR3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD276","classification":"Not Classified","n_dependent_lines":63,"n_total_lines":1208,"dependency_fraction":0.052152317880794705},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD276","total_profiled":1310},"omim":[{"mim_id":"613714","title":"NATURAL KILLER CELL CYTOTOXICITY RECEPTOR 3 LIGAND 1; NCR3LG1","url":"https://www.omim.org/entry/613714"},{"mim_id":"610784","title":"MICRO RNA 29C; MIR29C","url":"https://www.omim.org/entry/610784"},{"mim_id":"610783","title":"MICRO RNA 29B1; MIR29B1","url":"https://www.omim.org/entry/610783"},{"mim_id":"610782","title":"MICRO RNA 29A; MIR29A","url":"https://www.omim.org/entry/610782"},{"mim_id":"605715","title":"CD276 ANTIGEN; CD276","url":"https://www.omim.org/entry/605715"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD276"},"hgnc":{"alias_symbol":["B7-H3","B7H3","B7RP-2"],"prev_symbol":[]},"alphafold":{"accession":"Q5ZPR3","domains":[{"cath_id":"2.60.40.10","chopping":"32-140","consensus_level":"high","plddt":92.3768,"start":32,"end":140},{"cath_id":"2.60.40.10","chopping":"144-238","consensus_level":"medium","plddt":90.6679,"start":144,"end":238},{"cath_id":"2.60.40.10","chopping":"250-358","consensus_level":"medium","plddt":90.3152,"start":250,"end":358},{"cath_id":"2.60.40.10","chopping":"365-457","consensus_level":"high","plddt":90.3259,"start":365,"end":457}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5ZPR3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5ZPR3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5ZPR3-F1-predicted_aligned_error_v6.png","plddt_mean":83.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD276","jax_strain_url":"https://www.jax.org/strain/search?query=CD276"},"sequence":{"accession":"Q5ZPR3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5ZPR3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5ZPR3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5ZPR3"}},"corpus_meta":[{"pmid":"30655315","id":"PMC_30655315","title":"CAR 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B7-H3 deficiency in mTORC1-hyperactive tumors suppresses tumor growth through an immune-mediated mechanism involving increased T-cell activity, IFN-γ responses, and increased tumor cell MHC-II expression, with strikingly increased cytotoxic CD38+CD39+CD4+ T cells.\",\n      \"method\": \"Mechanistic experiments including phosphorylation assays, transcription factor identification, genetic KO models, CITE-seq, and in vivo tumor studies\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct phosphorylation mechanism identified, multiple orthogonal methods (CITE-seq, KO models, in vivo), single lab but rigorous mechanistic follow-up\",\n      \"pmids\": [\"36869048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FUT8 mediates core fucosylation of CD276 (B7-H3) at N104. FUT8-silence-induced defucosylation at N104 on B7-H3 causes HSC70 (HSPA8) to bind the 106-110 SLRLQ motif of B7-H3, propelling lysosomal proteolysis of B7-H3 through the chaperone-mediated autophagy (CMA) pathway via HSC70/LAMP2A.\",\n      \"method\": \"Mutagenesis, co-immunoprecipitation, lysosomal degradation assays, small-molecule inhibitor (FDW028), in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — specific N104 fucosylation site identified by mutagenesis, binding partner (HSC70) and degradation pathway (CMA/LAMP2A) established with orthogonal methods in single lab\",\n      \"pmids\": [\"37537172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lactate-upregulated histone H3K18 lactylation (H3K18la) directly binds to the B7-H3 promoter in conjunction with transcription factor Creb1 and co-activator Ep300, leading to increased B7-H3 expression and tumor immune evasion by reducing CD8+ T cell cytotoxicity.\",\n      \"method\": \"ChIP assay, LDHA knockdown, pharmacological glycolysis inhibition, in vivo tumor models, CD8+ T cell functional assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP identifies Creb1/Ep300 at B7-H3 promoter, mechanism validated with orthogonal inhibition approaches, single lab\",\n      \"pmids\": [\"39990209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by upregulating hexokinase 2 (HK2) expression. Depletion of HK2 or treatment with HK2 inhibitors reverses B7-H3-induced glycolysis and chemoresistance.\",\n      \"method\": \"B7-H3 overexpression/knockdown, glucose consumption and lactate production assays, HK2 siRNA and inhibitor experiments, in vitro functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined metabolic phenotype, HK2 identified as downstream effector with epistasis via siRNA and inhibitors, single lab\",\n      \"pmids\": [\"30952834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"B7-H3 promotes colorectal cancer angiogenesis by activating the NF-κB pathway to upregulate VEGFA expression. Conditioned medium from B7-H3 knockdown CRC cells inhibited HUVEC migration, invasion, and tube formation; recombinant VEGFA rescued this effect, and VEGFA siRNA or neutralizing antibody reversed B7-H3 overexpression effects.\",\n      \"method\": \"B7-H3 knockdown/overexpression, conditioned medium experiments on HUVECs, VEGFA siRNA and neutralizing antibody, NF-κB pathway inhibition, in vivo experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via NF-κB/VEGFA axis with multiple rescue experiments, single lab\",\n      \"pmids\": [\"31974361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B7-H3 (Cd276) knockout in tumor cells (but not stromal cells) suppresses ovarian cancer progression and reduces M2 macrophage number while increasing IFNγ+CD8+ T cells. B7-H3 expression drives immunosuppression via the CCL2-CCR2-M2 macrophage axis; CCL2 was downregulated in B7-H3 KO tumor cells, and inhibition of CCL2-CCR2 partly negated B7-H3 suppression effects on M2 macrophage migration/differentiation.\",\n      \"method\": \"Syngeneic mouse KO models (tumor cell-specific Cd276 KO), flow cytometry, transcriptome analysis, CCL2-CCR2 axis inhibition experiments\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tumor-cell-specific KO with defined immune phenotype, CCL2 mechanistic link established with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34799346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of PTEN and TP53 induces B7-H3 expression by activating transcription factor Sp1. Prostate-specific deletion of Cd276 in Pten/Trp53 genetically engineered mouse models delayed tumor progression and reversed suppression of tumor-infiltrating T cells and NK cells.\",\n      \"method\": \"Genetically engineered mouse models (GEMM), Sp1 transcription factor experiments, in vivo prostate-specific Cd276 deletion, immune cell phenotyping\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTEN/TP53-Sp1-B7-H3 transcriptional axis established in GEMM with prostate-specific KO and immune phenotyping, single lab with multiple methods\",\n      \"pmids\": [\"37163614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"B7-H3 promotes gastric cancer cell migration and invasion through interaction with CXCR4. B7-H3 silencing downregulated CXCR4 and inhibited AKT, ERK, and Jak2/Stat3 phosphorylation. Co-immunoprecipitation assays demonstrated a direct protein-protein interaction between B7-H3 and CXCR4, and immunofluorescence confirmed co-localization.\",\n      \"method\": \"shRNA-mediated B7-H3 silencing, co-immunoprecipitation, immunofluorescence co-localization, in vitro migration/invasion assays, in vivo metastasis model (tail vein injection)\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP establishes B7-H3/CXCR4 interaction, downstream signaling changes confirmed, in vivo validation, single lab\",\n      \"pmids\": [\"29069741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B7-H3 (CD276) is highly expressed in mouse and human adipose tissue, particularly in adipocyte progenitor cells, and is rapidly downregulated upon initiation of adipocyte differentiation. Loss of B7-H3 in progenitors results in impaired oxidative metabolism and increased lipid accumulation. B7-H3 knockout mice develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation.\",\n      \"method\": \"RNA sequencing, metabolic studies, B7-H3 KO mouse model, adipocyte differentiation assays, mitochondrial activity measurements\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with clear metabolic phenotype, RNA-seq and metabolic assays orthogonally support B7-H3 role in adipocyte progenitor metabolism, single lab\",\n      \"pmids\": [\"35476450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"B7-H3 regulates KIF15 expression (independent of NF-κB pathway, as revealed by RNA sequencing), and the B7-H3/KIF15 axis activates ERK1/2 signaling to confer radioresistance in colorectal cancer. siRNA-mediated KIF15 silencing or KIF15 inhibitor SB743921 abolished B7-H3-mediated radioresistance in vitro and in vivo.\",\n      \"method\": \"RNA sequencing, siRNA knockdown, specific KIF15 inhibitor (SB743921), B7-H3 blocking antibody (3E8) in vivo, colony formation assays, cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq identifies KIF15, epistasis confirmed via siRNA and pharmacological inhibitor, in vivo validation included, single lab\",\n      \"pmids\": [\"33011740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"B7-H3 increases thymidylate synthase (TS) expression via activation of the PI3K/Akt pathway, resulting in colorectal cancer cell resistance to 5-fluorouracil. The PI3K-specific inhibitor LY294002 blocked B7-H3-induced PI3K/Akt activation and TS upregulation.\",\n      \"method\": \"B7-H3 overexpression in SW480 and HCT8 cells, CCK-8 cell viability assays, Western blotting for TS and PI3K/Akt, pharmacological inhibition with LY294002\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibition places B7-H3 upstream of PI3K/Akt/TS, multiple cell lines, single lab\",\n      \"pmids\": [\"26787540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B7-H3 expression in pancreatic cancer is regulated at the transcriptional level by BRD4 (a BET bromodomain protein). BET inhibitors decreased B7-H3 protein and mRNA levels. Furthermore, the BRD4/B7-H3 axis modulates TLR4 expression in pancreatic cancer cells.\",\n      \"method\": \"BET inhibitor drug screening, BRD4 knockdown, RT-PCR and Western blotting for B7-H3 and TLR4, pancreatic cancer cell line experiments\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — BRD4 identified as transcriptional regulator of B7-H3 with pharmacological and siRNA evidence, downstream TLR4 pathway identified, single lab\",\n      \"pmids\": [\"30664982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"B7-H3 upregulates BRCC3 (a component of the BRCA1-BRCA2-BRCC3 DNA repair complex) expression, enhancing DNA repair and conferring resistance to 5-fluorouracil-induced DNA damage in colorectal cancer. BRCC3 knockdown in B7-H3-overexpressing cells permitted greater 5-Fu-induced DNA damage.\",\n      \"method\": \"mRNA microarray, RT-PCR, Western blotting, DNA comet assay for DNA damage, siRNA knockdown of BRCC3 in B7-H3 overexpressing cells\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via BRCC3 knockdown in B7-H3 overexpressing cells using DNA damage readout, multiple methods, single lab\",\n      \"pmids\": [\"27175567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD276 (B7-H3) knockdown in late endothelial progenitor cells (LEPCs) significantly decreased proliferation and migration while increasing apoptosis. CD276 knockdown caused cell cycle arrest at G0/G1, increased cyclin D2/D3/E1-CDK2/4/6, decreased cyclin A/B-CDK1, decreased pErk1/2 and pAkt. Paradoxically, CD276 KD increased tube formation and angiogenesis in vitro and in vivo, with upregulation of FoxC1/C2 and Hey1/2 (Notch arterial differentiation pathway) and VEGF-VEGFR1 and p-p38.\",\n      \"method\": \"Lentiviral knockdown, FACS cell cycle analysis, tube formation assay in vitro, Matrigel plug angiogenesis assay in vivo, Western blotting for signaling molecules\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lentiviral KD with multiple orthogonal readouts (proliferation, migration, angiogenesis, signaling), in vitro and in vivo confirmation, single lab\",\n      \"pmids\": [\"30379377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B7-H3 regulates osteoclast differentiation as a positive physiologic regulator. B7-H3 deficiency inhibits osteoclastogenesis in human osteoclast precursors (OCPs). Mechanistically, B7-H3 inhibition upregulates type-I IFN signaling and IFN-inducible IDO expression; pharmacological inhibition of type-I IFN or IDO knockdown reverses B7-H3-deficiency-mediated osteoclastogenesis suppression.\",\n      \"method\": \"High-throughput transcriptomics, pharmacological inhibition of type-I IFN, IDO knockdown, osteoclast differentiation assays in human OCPs\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomics identifies IFN-IDO axis, pharmacological and siRNA epistasis confirms pathway positioning, single lab\",\n      \"pmids\": [\"34671026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Stimulation of surface B7-H3 on human marrow stromal cells (hMSCs) with a specific anti-B7-H3 monoclonal antibody (4H7) promotes osteoblast differentiation, increasing alkaline phosphatase and osteocalcin markers and mineralized nodule formation. B7-H3 stimulation also increased OPG expression and decreased RANKL expression. This effect was abolished by addition of B7-H3-Fc fusion protein, confirming membrane B7-H3 specificity.\",\n      \"method\": \"Anti-B7-H3 mAb stimulation, B7-H3-Fc competitive blocking, osteoblast differentiation assays (ALP, osteocalcin, mineralized nodule quantification), Western blotting for OPG/RANKL\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody stimulation and Fc competitive blocking establish B7-H3 membrane function, multiple differentiation markers measured, single lab\",\n      \"pmids\": [\"21893365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SRSF3 splicing factor directly binds to B7-H3 mRNA and contributes to the retention of B7-H3 exon 4, thereby regulating B7-H3 expression in colorectal cancer. RNA immunoprecipitation (RIP) confirmed direct SRSF3-B7-H3 mRNA binding. Knockdown of SRSF3 reduced B7-H3 mRNA and protein, while SRSF3 overexpression increased B7-H3 expression.\",\n      \"method\": \"Individual knockdown of splicing factors, RNA immunoprecipitation (RIP), minigene construct with B7-H3 exons 3-6, qPCR and Western blotting\",\n      \"journal\": \"Cancer immunology, immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding established by RIP, minigene exon retention confirmed, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"32719950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBV infection induces B7-H3 expression in nasopharyngeal carcinoma (NPC) via activation of the PI3K/AKT/mTOR signaling pathway through EBV latent membrane protein 1 (LMP1). B7-H3 expression on EBV+ NPC tumor cells negatively correlates with and inhibits NK cell cytotoxic function in vitro and in vivo.\",\n      \"method\": \"EBV infection models, LMP1 expression constructs, PI3K/AKT/mTOR inhibitor experiments, NK cell cytotoxicity assays, NPC xenograft mouse model with adoptive NK cell transfer\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LMP1-PI3K/AKT/mTOR mechanism established with pathway inhibitors, in vitro and in vivo NK functional assays confirm B7-H3 immunosuppressive role, single lab\",\n      \"pmids\": [\"36996321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRC-derived exosomal B7-H3 is taken up by human umbilical vein endothelial cells (HUVECs) and activates the AKT1/mTOR/VEGFA signaling pathway, enhancing HUVEC migration, invasion, and tube formation, and promoting pulmonary angiogenesis and CRC metastasis in mice.\",\n      \"method\": \"Exosome isolation and uptake assays, AKT1/mTOR/VEGFA pathway analysis, HUVEC functional assays (migration, invasion, tube formation), in vivo CRC metastasis mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosomal B7-H3 uptake demonstrated, AKT1/mTOR/VEGFA pathway activation confirmed, in vivo validation, single lab\",\n      \"pmids\": [\"37263461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"B7-H3 promotes EMT in NSCLC by upregulating SIRT1 expression via the PI3K/AKT pathway. CRISPR/Cas9-mediated B7-H3 deletion downregulated SIRT1 and phosphorylated AKT in A549 cells, resulting in increased E-cadherin and decreased N-cadherin and vimentin. PI3K inhibitor LY294002 suppressed SIRT1 expression, placing B7-H3 upstream of PI3K/AKT/SIRT1 in this EMT pathway.\",\n      \"method\": \"CRISPR/Cas9 B7-H3 deletion, SIRT1 siRNA, PI3K inhibitor LY294002, Western blotting for EMT markers and signaling molecules, migration and invasion assays\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO and SIRT1 siRNA epistasis, pharmacological PI3K inhibition places B7-H3 in pathway, single lab\",\n      \"pmids\": [\"35029291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"B7-H3 inhibits apoptosis in gastric cancer cells through an FN (fibronectin)-dependent pathway. B7-H3 interacts with fibronectin and subsequently activates PI3K/AKT signaling, suppressing pro-apoptotic proteins (Caspase 3, 8, 9, Bax, p53, Apaf-1, Cleaved PARP) and upregulating Bcl-2.\",\n      \"method\": \"shRNA B7-H3 knockdown, bioinformatics correlation (TCGA), co-immunoprecipitation of B7-H3 and fibronectin, apoptosis protein expression by Western blot, exogenous FN rescue experiments\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP establishes B7-H3/FN interaction, multiple apoptosis markers measured, exogenous FN rescue confirms pathway dependence, single lab\",\n      \"pmids\": [\"35003371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fibronectin (FN) interacts with B7-H3 in clear cell renal cell carcinoma and promotes tumor metastasis by activating PI3K, AKT, p38, and ERK kinases. B7-H3 knockdown abolished the pro-metastatic effect of exogenous FN, establishing B7-H3 as a required mediator of FN-induced metastasis signaling.\",\n      \"method\": \"B7-H3 knockdown, exogenous FN treatment, co-immunoprecipitation/database correlation for B7-H3-FN interaction, migration/invasion assays, Western blotting for PI3K/AKT/p38/ERK\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — FN interaction confirmed, epistasis established by B7-H3 KD abolishing FN effects, single lab\",\n      \"pmids\": [\"34431237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"B7-H3 promotes cancer stem cell characteristics in gastric cancer through activation of the AKT/Nrf2/glutathione (GSH) metabolism pathway. B7-H3 knockdown suppressed stemness markers and GSH metabolism; inhibition of AKT signaling suppressed both GSH metabolism and GC stemness. Mass spectrometry identified downregulation of GSH metabolism in shB7-H3 cells.\",\n      \"method\": \"shRNA B7-H3 knockdown, B7-H3 overexpression, mass spectrometry metabolic profiling, Western blotting for AKT/Nrf2, sphere formation assays, multi-color IHC on human tissues, in vivo xenograft\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identifies GSH pathway, AKT/Nrf2 mechanistic axis confirmed, multiple methods including in vivo, single lab\",\n      \"pmids\": [\"37488673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B7-H3 promotes angiogenesis in endothelial cells (HUVECs) through enhancement of VEGF secretion. B7-H3 knockdown decreased HUVEC proliferation, migration, tube formation, and VEGF expression in vitro, and impaired functional vascular network formation in Matrigel plug assays in vivo.\",\n      \"method\": \"B7-H3 transient knockdown in HUVECs, VEGF ELISA, proliferation/migration/tube formation assays, in vivo Matrigel plug assay\",\n      \"journal\": \"Immunologic research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — KD with defined angiogenic phenotype and VEGF secretion as mechanism, in vitro and in vivo confirmed, single lab\",\n      \"pmids\": [\"31292886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"B7-H3 expression in CRPC is negatively regulated by androgen receptor (AR) during the early phase of ADT treatment, but is positively associated with PCa proliferation during subsequent disease progression. These findings were established using patient-derived xenograft (PDX) models longitudinally assessed during post-ADT progression and validated in clinical patient samples.\",\n      \"method\": \"Longitudinal study using PCa patient-derived xenograft (PDX) models with ADT treatment, immunohistochemistry on clinical patient samples\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — AR regulation of B7-H3 established in PDX models with longitudinal design and clinical validation, single lab\",\n      \"pmids\": [\"37452083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNA methylation of the B7-H3 promoter negatively regulates its expression; DNMT inhibition (decitabine) increased B7-H3 expression via demethylation of the B7-H3 locus. This was demonstrated in neuroendocrine prostate cancer and RB1-deficient CRPC models.\",\n      \"method\": \"DNMT gene deletion, decitabine treatment, B7-H3 expression analysis in patient-derived xenograft models, methylation analysis\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNMT deletion and pharmacological inhibition both increase B7-H3 via demethylation, tested in multiple models, single lab\",\n      \"pmids\": [\"37967200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"B7-H3 expressed on tumor cells suppresses CD8+ T-cell-mediated immune surveillance. Anti-B7-H3 blockade in a syngeneic murine cancer model increased CD8+ TIL numbers and restored effector function; CD8+ T-cell depletion negated this antitumor efficacy. Dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction beyond either agent alone.\",\n      \"method\": \"Anti-B7-H3 blocking antibody in syngeneic murine model, CD8+ T-cell depletion experiment, flow cytometry for TIL quantification and function, dual antibody blockade experiment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD8 depletion epistasis establishes mechanistic requirement, syngeneic model with functional immune readouts, single lab\",\n      \"pmids\": [\"29530936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse B7-H3 mediates antitumor immunity through CD8+ T cells and NK cells (with no contribution from CD4+ T cells). Intratumoral injection of a mouse B7-H3 expression plasmid caused complete regression of 50% of EL-4 lymphoma tumors and generated systemic immunity. CD8+ T cell and NK cell depletion experiments established the cellular requirements for B7-H3-mediated antitumor activity.\",\n      \"method\": \"Intratumoral plasmid injection in mouse EL-4 lymphoma model, immune cell depletion (CD8+ T cell, NK cell, CD4+ T cell), tumor rechallenge to assess systemic immunity\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immune cell depletion epistasis identifies required effector cells, tumor rechallenge confirms systemic immunity, single lab in vivo\",\n      \"pmids\": [\"12939639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GM-CSF, enriched in gastric cancer tumor tissue, induces B7-H3 expression on neutrophils via JAK-STAT3 signaling pathway activation, in both time-dependent and dose-dependent manners.\",\n      \"method\": \"Tumor culture supernatant experiments, GM-CSF dose-response and time-course experiments on neutrophils, JAK-STAT3 pathway inhibition, flow cytometry\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — dose-dependent GM-CSF induction of B7-H3 via JAK-STAT3 confirmed with pharmacological inhibition, single lab\",\n      \"pmids\": [\"33945871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"B7-H3 confers β-catenin-dependent co-localization; β-catenin co-localizes with B7-H3 and promotes its expression in adamantinomatous craniopharyngiomas, as shown by immunofluorescence and Western blot analysis.\",\n      \"method\": \"Immunofluorescence co-localization, Western blot analysis, immunohistochemistry on 44 craniopharyngioma samples\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization by IF only, no direct interaction assay or mechanistic epistasis confirmed, single lab\",\n      \"pmids\": [\"31043272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAR T cells based on camel nanobodies recognizing the IgC domain (but not the IgV domain) of B7-H3 had more potent antitumor activity than IgV-targeting nanobody CAR-T cells. Single-cell RNA sequencing and T-cell proteomics identified top upregulated genes critical for polyfunctional CAR-T cell persistence, establishing the IgC epitope as optimal for CAR activation.\",\n      \"method\": \"Camel nanobody generation targeting IgC vs IgV epitopes, CAR-T cell construction, in vivo antitumor efficacy in mice, single-cell RNA sequencing, T-cell proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitope domain comparison with scRNA-seq and proteomics, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37739951\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD276 (B7-H3) is a type I transmembrane glycoprotein of the B7 immune checkpoint family whose expression is transcriptionally regulated by Sp1 (downstream of PTEN/TP53 loss), BRD4, SRSF3-mediated mRNA splicing, promoter methylation/demethylation, mTORC1-driven YY2 phosphorylation by S6K, and lactate-induced H3K18 lactylation recruiting Creb1/Ep300 to its promoter; at the protein level, FUT8-mediated core fucosylation at N104 stabilizes B7-H3 by preventing HSC70/LAMP2A-mediated chaperone-mediated autophagy degradation. B7-H3 suppresses antitumor immunity by inhibiting CD8+ T cell and NK cell activity, driving M2 macrophage polarization via the CCL2-CCR2 axis, and its deletion in tumors relieves immunosuppression and slows cancer progression. Non-immunologically, B7-H3 promotes glycolysis via HK2, drug resistance via BRCC3-mediated DNA repair, radioresistance via KIF15/ERK1/2, EMT via PI3K/AKT/SIRT1, angiogenesis via NF-κB/VEGFA and VEGF secretion from endothelial cells, metastasis by interacting with CXCR4 and fibronectin to activate PI3K/AKT, and cancer stemness via AKT/Nrf2/GSH metabolism; it also regulates osteoblast differentiation and positively controls osteoclastogenesis through suppression of type-I IFN/IDO signaling, and in adipose progenitors it sustains oxidative metabolism such that B7-H3 KO mice develop spontaneous obesity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD276 (B7-H3) is a cell-surface immune checkpoint molecule that suppresses antitumor immunity while concurrently driving tumor-intrinsic programs of metabolism, survival, and metastasis [#26, #27]. Tumor-cell B7-H3 restrains CD8+ T-cell and NK-cell effector function: antibody blockade increases tumor-infiltrating CD8+ T cells and restores their cytotoxicity, an effect lost upon CD8+ T-cell depletion and enhanced by dual PD-L1 blockade [#26], and its forced expression in mouse tumors mediates regression dependent on both CD8+ T cells and NK cells [#27]. B7-H3 also reshapes the myeloid compartment, promoting M2 macrophage recruitment and differentiation through tumor-cell CCL2 acting on the CCL2-CCR2 axis [#5], and inhibits NK cytotoxicity in EBV-driven nasopharyngeal carcinoma [#17]. Its expression is tightly controlled at multiple levels: transcriptionally by Sp1 downstream of PTEN/TP53 loss [#6], by BRD4 [#11], by androgen receptor in prostate cancer [#24], by promoter DNA methylation reversed by DNMT inhibition [#25], and by lactate-driven H3K18 lactylation recruiting Creb1/Ep300 to its promoter [#2]; by mTORC1 via S6K-mediated phosphorylation of YY2 [#0]; post-transcriptionally by SRSF3-dependent exon 4 retention [#16]; and post-translationally by FUT8-mediated core fucosylation at N104, which prevents HSC70/LAMP2A-mediated chaperone-mediated autophagy degradation [#1]. Independent of immune modulation, B7-H3 acts as a tumor-cell signaling hub that engages partners including CXCR4 and fibronectin to activate PI3K/AKT signaling driving migration, invasion, EMT, apoptosis resistance, and stemness [#7, #20, #21, #22], promotes aerobic glycolysis via HK2 [#3], confers chemo- and radioresistance via BRCC3-mediated DNA repair and a KIF15/ERK1/2 axis [#12, #9], and stimulates angiogenesis through NF-\\u03baB/VEGFA and VEGF secretion [#4, #23]. Beyond cancer, B7-H3 is a physiologic regulator of bone and metabolism: it promotes osteoblast differentiation and positively controls osteoclastogenesis by suppressing type-I IFN/IDO signaling [#15, #14], and sustains oxidative metabolism in adipocyte progenitors such that its loss produces spontaneous obesity in mice [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established which immune effectors mediate B7-H3-dependent antitumor activity, defining its immunological function before downstream mechanisms were known.\",\n      \"evidence\": \"Intratumoral B7-H3 plasmid injection with CD8+ T-cell, NK-cell, and CD4+ T-cell depletion in mouse EL-4 lymphoma\",\n      \"pmids\": [\"12939639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Plasmid overexpression context; relationship to endogenous tumor B7-H3 immunosuppression unresolved\", \"Receptor on T/NK cells not identified\", \"Costimulatory vs coinhibitory role context-dependent\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed B7-H3 has a non-immune physiologic role by demonstrating membrane B7-H3 stimulation drives osteoblast differentiation and shifts OPG/RANKL balance.\",\n      \"evidence\": \"Anti-B7-H3 mAb stimulation with B7-H3-Fc competitive blocking in human marrow stromal cells\",\n      \"pmids\": [\"21893365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Counter-receptor for membrane B7-H3 unknown\", \"Intracellular signaling pathway not defined\", \"Antibody agonism may not mimic physiologic ligand\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified tumor-intrinsic, immune-independent mechanisms of chemoresistance, recasting B7-H3 as a signaling effector inside tumor cells.\",\n      \"evidence\": \"B7-H3 overexpression/knockdown with PI3K/Akt inhibition (LY294002), BRCC3 siRNA, and DNA comet assays in colorectal cancer cells\",\n      \"pmids\": [\"26787540\", \"27175567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How surface B7-H3 transduces intracellular PI3K/AKT signal unclear\", \"No structural basis for signaling\", \"Single lineage (CRC)\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a direct physical partner (CXCR4) linking B7-H3 to pro-metastatic kinase signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence co-localization, and shRNA knockdown with migration/metastasis assays in gastric cancer\",\n      \"pmids\": [\"29069741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal Co-IP or domain mapping\", \"Direct vs complex-mediated interaction unconfirmed\", \"Stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined endogenous tumor B7-H3 as a CD8+ T-cell checkpoint amenable to combination blockade, anchoring its therapeutic rationale.\",\n      \"evidence\": \"Anti-B7-H3 blocking antibody with CD8+ depletion and PD-L1 co-blockade in a syngeneic murine model\",\n      \"pmids\": [\"29530936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"T-cell receptor for B7-H3 not identified\", \"Single model\", \"Molecular signal delivered to T cells unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded the tumor-intrinsic repertoire to metabolic reprogramming and angiogenesis, and identified BRD4 as a transcriptional driver.\",\n      \"evidence\": \"Knockdown/overexpression with HK2 inhibition, NF-\\u03baB inhibition and VEGFA rescue, VEGF ELISA, and BET inhibitor/BRD4 knockdown across CRC and pancreatic models\",\n      \"pmids\": [\"30952834\", \"31974361\", \"31292886\", \"30664982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether glycolytic, angiogenic and transcriptional axes are mechanistically linked unresolved\", \"Effects largely correlative across separate single-lab studies\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established post-transcriptional control of B7-H3 by SRSF3 and a radioresistance pathway via KIF15/ERK1/2.\",\n      \"evidence\": \"RNA immunoprecipitation and minigene exon-retention assays for SRSF3; RNA-seq, KIF15 siRNA/inhibitor SB743921 with in vivo radiation in CRC\",\n      \"pmids\": [\"32719950\", \"33011740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of exon 4 retention on protein not detailed\", \"How B7-H3 regulates KIF15 transcription unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the myeloid arm of immunosuppression (CCL2-CCR2-M2) and demonstrated fibronectin as a B7-H3 partner driving PI3K/AKT survival and metastasis signaling.\",\n      \"evidence\": \"Tumor-cell-specific Cd276 KO with CCL2-CCR2 inhibition in ovarian cancer; Co-IP of B7-H3 with fibronectin and exogenous-FN rescue in gastric and renal carcinoma\",\n      \"pmids\": [\"34799346\", \"35003371\", \"34431237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface for fibronectin not mapped\", \"CCL2 regulation mechanism downstream of B7-H3 not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended physiologic roles to bone homeostasis, showing B7-H3 positively controls osteoclastogenesis through suppression of type-I IFN/IDO.\",\n      \"evidence\": \"Transcriptomics with type-I IFN inhibition and IDO knockdown in human osteoclast precursors\",\n      \"pmids\": [\"34671026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which B7-H3 suppresses IFN signaling unknown\", \"Reconciliation with osteoblast-promoting role not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an organismal metabolic function in adipose progenitors, demonstrating B7-H3 sustains oxidative metabolism with KO mice developing spontaneous obesity.\",\n      \"evidence\": \"RNA-seq, mitochondrial/metabolic assays, and B7-H3 KO mouse phenotyping in adipocyte progenitors\",\n      \"pmids\": [\"35476450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector linking B7-H3 to oxidative metabolism unidentified\", \"Cell-autonomous vs systemic contribution unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Integrated upstream regulation across transcription (Sp1/PTEN-TP53, methylation), translation/signaling (mTORC1-S6K-YY2), and protein stability (FUT8 fucosylation/CMA), explaining how B7-H3 levels are set.\",\n      \"evidence\": \"GEMM with Sp1 axis and prostate-specific Cd276 KO; mTORC1/S6K phosphorylation of YY2 with CITE-seq and KO; FUT8 N104 mutagenesis with HSC70 Co-IP and CMA degradation assays; DNMT deletion/decitabine demethylation\",\n      \"pmids\": [\"37163614\", \"36869048\", \"37537172\", \"37967200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk among these regulatory inputs not integrated\", \"Relative contribution of each in different tumor types unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened tumor-intrinsic signaling to EMT (PI3K/AKT/SIRT1), stemness (AKT/Nrf2/GSH), and exosome-mediated angiogenesis, and identified viral and AR-dependent expression control.\",\n      \"evidence\": \"CRISPR KO with LY294002 (EMT); mass spectrometry and AKT/Nrf2 analysis (stemness); exosome uptake and AKT1/mTOR/VEGFA assays; EBV-LMP1/PI3K-AKT-mTOR and PDX/ADT-AR models\",\n      \"pmids\": [\"35029291\", \"37488673\", \"37263461\", \"36996321\", \"37452083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Convergence of multiple AKT-centric phenotypes onto a single mechanism unresolved\", \"Many readouts single-lineage and correlative\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected metabolic state to B7-H3 transcription via lactate-driven histone lactylation, linking the tumor metabolic environment to immune evasion.\",\n      \"evidence\": \"ChIP for H3K18la/Creb1/Ep300 at the B7-H3 promoter, LDHA knockdown, glycolysis inhibition, and CD8+ T-cell assays in vivo\",\n      \"pmids\": [\"39990209\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal chain from lactate to promoter occupancy needs orthogonal confirmation\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The bona fide receptor(s) that B7-H3 engages on T and NK cells to deliver its inhibitory signal remains unidentified, leaving the core mechanism of immune checkpoint function undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No counter-receptor identified in the corpus\", \"How a cell-surface checkpoint also acts as an intracellular PI3K/AKT signaling node is unresolved\", \"No structural model of B7-H3 in ligand/receptor complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [26, 27, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [7, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [15, 26, 30]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 27, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 20, 21, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 8, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 11, 2, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CXCR4\", \"FN1\", \"HSPA8\", \"FUT8\", \"LAMP2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}