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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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1837397","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:46:26Z","timestamp":1778647586000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["B7-H4: a multifaceted immune checkpoint and oncoprotein in cancer biology and immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Chunyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Zhangjiagang, 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