Drug discovery strategies targeting B7-H3 (CD276) in lung and gastric cancers: From biological validation to next-generation small molecules, biologics and cell-based immunotherapies.

B7 homolog 3 protein (B7-H3, also known as CD276) has emerged as a promising immune checkpoint target because of its high expression in solid tumors, limited presence in normal tissues and roles in immune evasion and tumor progression. This review focuses on the biological and therapeutic relevance of B7-H3 in lung and gastric cancers, where it contributes to oncogenic signaling, epithelial-mesenchymal transition, metabolic reprogramming and therapy resistance. We highlight its structural biology, target validation and molecular mechanisms while critically assessing therapeutic strategies, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, CAR-based therapies and emerging small-molecule inhibitors. We also discuss biomarkers, medicinal chemistry and future directions for precision cancer therapy.