B7 homolog 3 (B7-H3)

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 signal transducer and activator of transcription 3 (STAT3) signaling — as well as the Phosphatidylinositol 3-kinase (PI3K) (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.

Recent Publications Summary

Recent studies have continued to position B7 homolog 3 (B7-H3, CD276) as a versatile target across solid tumors, with applications spanning cell therapy, antibody-drug conjugates, and molecular imaging. In neuroblastoma, combining B7-H3 CAR T cells with VLA-4-targeted radiopharmaceutical therapy enhanced antitumor activity in both radio-sensitive and radio-resistant models, with effects attributed to direct tumor sensitization, TNF-α–linked pro-immune signaling, and remodeling of the tumor microenvironment (TME) 42335901Jun. In glioblastoma, B7-H3-targeted CAR T cells were further engineered to secrete an EGFR-directed bispecific T-cell engager, enabling dual targeting of B7-H3 and EGFR and improving control of heterogeneous tumors; sustained B7-H3 CAR exposure also reduced B7-H3 while increasing EGFR expression, suggesting antigen escape and adaptive antigen switching 42301527Jun. A separate preclinical study reported that fully human B7-H3 CAR constructs based on the Y111 binder outperformed earlier murine-derived 376.96- and MGA271-based CARs in pancreatic cancer, neuroblastoma, and glioblastoma xenografts, producing complete responses, tumor rejection, and survival benefit 42061408Apr. An allogeneic “off-the-shelf” B7-H3-targeted CAR Vδ1 T-cell therapy (UTAA06) has also entered phase I testing in advanced B7-H3-positive solid tumors 41779003Mar.

B7-H3 has also been explored as an imaging biomarker and surgical target. A clinical-grade anti-B7-H3 antibody conjugated to IRDye 800CW enabled fluorescence-guided surgery in rhabdomyosarcoma models, showing specific binding in B7-H3-expressing sarcoma cell lines and improved in vivo tumor visualization compared with control probes 42276839Jun. For noninvasive quantification, three 68Ga-labeled B7-H3-specific bicyclic peptide tracers were developed for immuno-PET; the lead tracer, [68Ga]Ga-B7H3-FZ1, showed the highest affinity and tumor uptake that correlated with B7-H3 expression across tumor models, including increased uptake in B7-H3-overexpressing H1299 tumors 42263262Jun. In medullary thyroid carcinoma, immunohistochemical profiling identified membranous B7-H3 expression in 91% of tumors, supporting its candidacy as a therapeutic surface antigen 42227355Jun.

Additional studies linked B7-H3 to therapeutic resistance and tumor biology. In hepatocellular carcinoma, CD276 was shown to promote tyrosine kinase inhibitor resistance by cooperating with pSTAT3 in the nucleus to drive CD36 transcription, increasing fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation; CD36 inhibition resensitized resistant cells 41956200Apr. In colorectal cancer organoids, immune-resistant subtypes exhibited significantly higher B7-H3 expression and altered phospholipid metabolism, with MSI analyses suggesting preservation of a larger phospholipid pool during immune challenge 41920069Apr. In metastatic prostate cancer, plasma extracellular vesicle proteomics identified B7-H3 among cell-surface proteins whose higher levels were associated with worse overall survival and correlated with PSMA-PET tumor burden and serum markers 42013849Apr. Reviews of pediatric solid tumors likewise highlighted B7-H3 among the leading targets for next-generation antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell strategies 41984108Apr.

What Changes, What Holds

1. B7-H3 now looks like a tractable therapeutic platform rather than only a tumor marker
REINFORCES These studies extend the established view of CD276 as a high-priority oncologic target by showing that multiple B7-H3-directed cell therapies can be strengthened, combined, or redesigned to improve control of difficult solid tumors 42335901Jun42301527Jun. The fully human binder data also sharpen the case for translational development by suggesting better activity than earlier CAR formats 42061408Apr. The phase I entry of an allogeneic product supports clinical feasibility, but the core baseline claim of broad tumor targeting remains unchanged 41779003Mar.

2. B7-H3 is becoming useful for imaging and surgical guidance, not just therapy
NEW DIRECTION These findings add a role the Overview does not cover: CD276 as a biomarker for noninvasive detection and intraoperative visualization 42276839Jun42263262Jun. That expands its utility beyond immune checkpoint biology and tumor targeting into diagnosis and procedure support. The medullary thyroid carcinoma expression data further reinforce surface accessibility, but they do not alter the baseline account of tumor-selective overexpression; they mainly strengthen the rationale for using B7-H3 as a visible target 42227355Jun.

3. CD276 may also drive resistance through metabolic rewiring, which complicates its role as a simple target
NEW DIRECTION The new hepatocellular carcinoma work adds a mechanism not described in the Overview: nuclear cooperation with pSTAT3 to induce CD36, lipid uptake, and fatty acid oxidation as a route to tyrosine kinase inhibitor resistance 41956200Apr. That does not contradict the baseline’s immune-evasion and signaling roles, but it broadens them into drug resistance biology. The colorectal and prostate findings similarly connect higher B7-H3 to resistant or aggressive states, yet they remain correlative and would need functional validation before being folded into the core account 41920069Apr42013849Apr.