B7-H3-mediated immune regulation in cancer: biological functions and therapeutic opportunities

Abstract

B7-H3 (CD276), a member of the B7 family of immunoregulatory ligands, has emerged as an important molecule at the intersection of tumor biology and cancer immunology. Although initially identified as a regulator of T-cell responses, accumulating evidence supports its predominantly immunosuppressive role. B7-H3 is highly expressed across diverse malignancies, including brain, prostate, lung, breast, colorectal, and pediatric cancers, while showing limited expression in most normal adult tissues. Its tumor-associated expression, including tumor vasculature, makes B7-H3 an attractive therapeutic target. Beyond immune regulation, B7-H3 promotes tumor progression through tumor cell-intrinsic mechanisms involving PI3K/AKT, NF-κB, and STAT3 signaling, angiogenesis, epithelial-to-mesenchymal plasticity, and metabolic reprogramming. Within the tumor microenvironment, B7-H3 suppresses T-cell and natural killer cell activity and promotes immunosuppressive macrophage polarization, while its expression can be regulated by metabolic and epigenetic mechanisms. These multifaceted functions have stimulated the development of diverse B7-H3-targeted therapies, including monoclonal antibodies, antibody-drug conjugates, CAR T-cell and Vδ1 T-cell therapies, nanobody-based platforms, and bispecific or trispecific immune cell engagers. Early clinical studies have demonstrated promising antitumor activity, although important challenges regarding efficacy, safety, tumor heterogeneity, and patient selection remain. In this review, we summarize the molecular regulation and biological functions of B7-H3, critically evaluate the current development of B7-H3-targeted therapies, and discuss key challenges and future directions for translating B7-H3-directed strategies into effective cancer treatments.