VSIG4 (V-set and immunoglobulin domain containing 4) is a type I transmembrane receptor exclusively expressed on tissue-resident macrophages that functions as a phagocytic receptor and potent immune suppressor 1. Mechanistically, VSIG4 binds complement component C3b to mediate clearance of opsonized pathogens 2 and suppresses T-cell proliferation and IL-2 production while promoting regulatory T-cell differentiation 1. In cancer, VSIG4+ tumor-associated macrophages (TAMs) create an immunosuppressive microenvironment through multiple pathways: promoting M2 macrophage polarization via fatty acid oxidation and JAK2/STAT3 signaling 3, reducing antigen presentation to CD8+ T cells 4, and inducing IL-11 transcription in TAMs 5. VSIG4 expression is upregulated in glioblastoma, pancreatic cancer, anaplastic thyroid cancer, and colorectal cancer, correlating with poor prognosis 645. The transcription factor MEF2C maintains VSIG4 expression in TAMs 5. Clinically, VSIG4 blockade or deficiency significantly reduces tumor growth and metastasis, with synergistic effects when combined with immune checkpoint inhibitors or targeted therapies 435. Additionally, VSIG4 has been identified as a biomarker in heart failure pathogenesis 7.