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CD276

CD276

Overview

CD276, widely known as B7-H3, is a type I transmembrane glycoprotein and a member of the B7 immune checkpoint ligand superfamily. Originally described as a co-stimulatory molecule, B7-H3 has since been characterized as a multifunctional regulator of adaptive immunity with a pronounced role in tumor biology. Structurally, the human isoform exists predominantly in a 4Ig configuration (containing four immunoglobulin-like domains), and its expression pattern is notably tumor-selective: comprehensive bioinformatics and histopathological analyses have confirmed marked upregulation of B7-H3 across a wide spectrum of malignancies, while expression in healthy tissues remains minimal. This differential expression profile has made CD276 one of the most attractive oncological targets under active clinical and preclinical investigation.

At the cellular level, B7-H3 functions as a multifunctional promoter of tumor progression, influencing immune evasion, signal transduction, and metabolic reprogramming within the tumor microenvironment. Recent evidence implicates B7-H3 in exosome biogenesis, suggesting an additional mechanism by which tumor cells exploit this protein to modulate intercellular communication and shape immune resistance. Its interactions with canonical oncogenic pathways — including nuclear factor kappa B (NF-κB) and STAT3 signaling — as well as the phosphatidylinositol 3-kinase (PI3K) axis, further underscore its role as a node connecting immune checkpoint function to intracellular proliferative and survival programs. The combination of broad tumor overexpression, low normal-tissue toxicity risk, and mechanistic involvement in immune evasion positions CD276 as a high-priority target for next-generation immunotherapies.

Focus of Latest Publications

Recent research demonstrates that CD276 (B7-H3) has emerged as a versatile therapeutic target across multiple solid tumor types, including rhabdomyosarcoma, glioblastoma, neuroblastoma, pancreatic cancer, small cell lung cancer, prostate cancer, and colorectal cancer. The convergence of multiple therapeutic modalities—from antibody-based imaging agents to engineered cellular therapies—reflects the growing clinical significance of B7-H3 in oncology. Notably, CD276 expression is associated with immunologically challenging tumor phenotypes, including immune-resistant colorectal cancer organoids, which display markedly elevated B7-H3 levels and altered phospholipid metabolism.

CAR-T cell engineering against CD276 represents a major clinical focus. Early candidates derived from murine monoclonal antibodies (376.96 and MGA271) have advanced to phase 1/2 trials, but recent work addresses their immunogenicity through fully human scFv design. Lead human binder Y111 incorporated into CAR-T cells demonstrates complete tumor responses and survival benefits in pancreatic, neuroblastoma, and glioblastoma xenografts, with superior efficacy compared to murine-derived constructs. Complementary approaches include allogeneic B7-H3-targeted CAR Vδ1T-cell therapy (UTAA06), designed as an off-the-shelf therapeutic for pretreated advanced B7-H3-positive tumors.

Intraoperative molecular imaging using CD276-directed antibodies enables real-time surgical guidance. Anti-B7-H3 antibody conjugates labeled with near-infrared fluorophores achieve substantially improved tumor visualization, enabling clear delineation of tumor margins, distinction from surrounding tissue, and detection of micrometastatic lesions in sarcoma models. Parallel advances in CAR-T cell tracking employ dual-modality labeling strategies combining second near-infrared window fluorescence imaging with magnetic resonance imaging, allowing longitudinal biodistribution profiling following intracranial administration in glioma models.

CD276 also functions as a potential prognostic biomarker. Elevated CD276 expression in circulating extracellular vesicles correlates with worse overall and progression-free survival in metastatic prostate cancer patients undergoing targeted radionuclide therapy, with levels associating with molecular tumor burden and serum markers of disease severity. These findings support integrating CD276 assessment into biomarker-driven patient stratification for multimodal immunotherapy trials.

Key Publications

  • NEWJun Biomedical publication details. (PubMed Database, 2026, PMID 42276839)
  • May Dual-modality imaging enables longitudinal biodistribution profiling of intracerebroventricular CAR-T therapy in orthotopic glioma. (Cancer immunology, immunotherapy : CII, 2026, PMID 42068336): "Here, we report a dual-modality cell labeling and tracking strategy based on indocyanine green-conjugated iron nanoparticles (ICG-NPs) for in vivo assessment of B7-H3-targeting CAR-T cell (TX103) biodistribution using second near-infrared window (NIR-II) fluorescence imaging and magnetic resonance imaging (MRI)."
  • May Engineering functionality-optimized fully human B7-H3 CAR T cells for enhanced solid tumor therapy. (Cell reports. Medicine, 2026, PMID 42061408): "B7-H3 is a cell surface protein overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR) T cell therapy."
  • Jun Comparative analysis of therapeutic target protein expression in de novo and transformed small cell lung carcinomas using paired biopsy samples. (Lung cancer (Amsterdam, Netherlands), 2026, PMID 42013561): "...data on other targetable proteins such as trophoblast cell-surface antigen 2 (TROP2) and B7-H3 remain limited."
  • May Plasma extracellular vesicle proteomics nominates candidate biomarkers of 177Lu-PSMA-617 outcomes in metastatic prostate cancer patients. (Cell reports. Medicine, 2026, PMID 42013849): "We identify 5,137 EV-derived proteins, including the cell-surface targets PSMA, B7-H3, Trop-2, and STEAP1, with high levels of these proteins associating with worse overall survival (OS)."
  • Apr Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations. (Cancer immunology, immunotherapy : CII, 2026, PMID 41984108): "...bispecific T cell engagers targeting GD2, B7-H3, and GPC2 are extending the reach of antibody-based approaches across pediatric histologies."
  • Apr Integrating Mass Spectrometry Imaging with Tumor Organoid-Immunity Platform to Identify Metabolic Adaptations in Tumor Immune Resistance. (Analytical chemistry, 2026, PMID 41920069): "...the resistant fraction exhibits significantly elevated B7-H3 expression."
  • May Allogeneic B7-H3-Targeted CAR Vδ1T-cell Therapy in Advanced Solid Tumors: A Phase I Study. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41779003): "...allogeneic B7-H3-targeted chimeric antigen receptor (CAR) Vδ1T-cell therapy..."
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