B7-H3/CD276: Novel Immune Checkpoint and Jack of All Trades

Abstract

Immunotherapy has transformed cancer treatment and outcomes, although resistance mechanisms remain challenging, prompting exploration of additional immune targets, including B7-H3/CD276. Indeed, B7-H3/CD276's complex and contrasting functions mark it as a jack of all trades, challenging conventional classifications of immune markers. B7-H3/CD276 is a protein belonging to the B7 family of immune regulatory molecules. It participates in immune response modulation and has been implicated in both immune activation and suppression, depending on the context though its precise immune function remains incompletely defined. B7-H3/CD276 expression is observed in various cancers and inflammatory conditions. In regard to cancer, there appears to be variability in expression both between and within malignancy types. B7-H3/CD276 targeting therapies have shown promising evidence of activity, particularly in patients over-expressing the B7-H3/CD276 protein based on immunohistochemistry. Here, we detail B7-H3/CD276's proposed immunologic and metabolic roles in the pathogenesis and progression of cancer, describe its heterogeneous patterns of RNA expression in a pan-cancer cohort, and summarize early clinical trial outcomes data.

Keywords: Targeted therapy; cancer immunotherapy; immune modulation; precision oncology; tumor heterogeneity; tumor microenvironment.

Figure 1

Immune and non-immune roles of B7-H3/CD276, the effects of blockade, and methods of targeting it. (A) The below figure illustrates the co-stimulatory and co-inhibitory immune and non-immune effects of B7-H3/CD276 signaling that lead to immune evasion of tumor cells (left) and the proposed antitumor effects of B7-H3/CD276 blockade (right). Although TLT-2 (myeloid cell-like transcript 2) has been identified as a likely co-stimulatory receptor, leading to activation of inactive CD8+ T cells, robust pre-clinical and clinical evidence of B7-H3/CD276’s role in immune evasion of cancer cells suggests the presence of additional co-inhibitory receptors. As shown on the right side of the figure, Wang et al found that blockade of B7-H3/CD276 inhibited tumor growth and eliminated cancer stem cells via enhancement of CD8+ T cell antitumor immunity as well as natural killer (NK) cell and T regulatory cell accumulation. As depicted within the cancer cell, B7-H3/CD276 may also exert protumorigenic effects such as cell survival, proliferation, chemoresistance, and enhanced glycolysis via non-immune mechanisms. Created in BioRender. Larkin, B (2025) https://BioRender.com/d41u645. (B) Examples are illustrated of the mechanisms employed to target B7-H3/CD276 on tumor cells including CAR-T cell therapy, antibody drug conjugates, and monoclonal antibodies. Created in BioRender. Larkin, B (2025) https://BioRender.com/pbsgx9v.

Figure 2

Proportion of patients exhibiting high B7-H3/CD276 expression. (A) Distribution of B7-H3/CD276 expression (n = 514). Above each column is listed the number of patients falling within each percentile rank. Of the 514 total patients, 214 (41.6%) demonstrated “high” expression of B7-H3/CD276 defined as RNA expression ≥75^th percentile rank. (B) Proportion of patients with high (≥ 75^th percentile rank) and low (< 75^th percentile rank) B7-H3/CD276 expression across cancer types. The patterns of B7-H3/CD276 expression across cancer types are shown below (n = 514). Among the various cancer types assessed, elevated RNA expression of B7-H3/CD276 was most frequently observed in patients with sarcoma (58.30%, 14/24), pancreatic cancer (58.20%, 32/55), and liver and bile duct cancer (52.60%, 10/19). Immunohistochemical analysis data from Zhang et al is listed below the figure for comparison between our studies. Patterns of B7-H3/CD276 expression in cancer types with sample sizes <10 are included in Supplementary Figure 1.