B7-H4: a multifaceted immune checkpoint and oncoprotein in cancer biology and immunotherapy

Immunotherapy has become a cornerstone of modern oncology. While immune checkpoint inhibitors have achieved transformative outcomes across multiple cancers, a substantial proportion of patients exhibit primary or acquired resistance, highlighting the need to identify novel immune regulatory pathways. The B7 family member B7-H4 (VTCN1) has emerged as a pivotal co-inhibitory checkpoint that is frequently overexpressed in various solid malignancies. It exerts potent immunosuppressive effects by impairing T-cell function and shaping an immunosuppressive tumor microenvironment. Concurrently, B7-H4 drives tumor-intrinsic oncogenic programs, promoting cell cycle progression, epithelial-mesenchymal transition, stemness, and resistance to therapy. Clinically, elevated B7-H4 levels correlate strongly with advanced cancer stage, metastasis, and poor prognosis, underscoring its dual utility as a prognostic biomarker and a compelling therapeutic target. Consequently, B7-H4-directed therapies, including monoclonal antibodies, bispecific T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T cells, hold significant potential to improve outcomes for cancer patients.