Prognostic and therapeutic roles of B7-H3 and B7-H4 in prostate cancer

Prostate cancer (PCa) remains a leading cause of cancer-related morbidity and mortality in men worldwide, with metastatic castration-resistant prostate cancer (mCRPC) presenting a particularly formidable therapeutic challenge. The limited efficacy of conventional immunotherapies targeting the PD-1/PD-L1 axis in PCa has spurred intensive research into alternative immune checkpoints. Among the B7 family of immunomodulatory proteins, B7-H3 (CD276) and B7-H4 (VTCN1/B7x/B7S1) have emerged as critical regulators of PCa pathogenesis, progression, and therapeutic resistance. This comprehensive review synthesizes current evidence from preclinical and clinical studies to delineate the multifaceted roles of B7-H3 and B7-H4 in PCa. We first detail the expression patterns of these molecules in PCa tissues and their robust correlation with adverse clinicopathological features, including high Gleason score, advanced tumor stage, metastasis, and poor survival outcomes. We then explore the complex molecular mechanisms underlying their pro-tumorigenic functions, encompassing immune suppression (inhibition of T-cell activity, modulation of myeloid-derived suppressor cells MDSCs and tumor-associated macrophages TAMs) and non-immune effects (regulation of cancer stem cells CSCs, DNA damage repair DDR, androgen receptor AR signaling, and tumor dormancy). Furthermore, we systematically review the rapidly expanding landscape of therapeutic strategies targeting B7-H3 and B7-H4, including antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, monoclonal antibodies, bispecific agents, and combination therapies with radiotherapy, AR pathway inhibitors (ARPIs), or other immunotherapies. We also discuss emerging directions such as liquid biopsy for B7-H3 detection, B7-H4-targeted immunoPET imaging, racial disparities in B7-H3 expression, and the development of predictive biomarkers for treatment response. Collectively, this review establishes B7-H3 and B7-H4 as pivotal nodes in PCa biology and highlights their promising potential to improve the clinical management of advanced and treatment-resistant PCa through improved prognostic stratification and the development of novel precision therapies.