V-set and immunoglobulin domain-containing protein 4 (VSIG4) (VSIG4)

V-set and immunoglobulin domain-containing protein 4 (VSIG4), also known as Complement Receptor of the Immunoglobulin superfamily (CRIg), is a type I transmembrane protein and a member of the B7 family-related proteins [14, 15]. It is primarily expressed on resting tissue-resident macrophages, such as Kupffer cells in the liver and alveolar macrophages in the lung, as well as on tumor-associated macrophages (TAMs) [19, 23]. VSIG4 serves a dual biological role: it acts as a potent negative regulator of T-cell activation, inhibiting T-cell proliferation and cytokine production, and functions as a complement receptor that binds C3b and iC3b to facilitate the phagocytosis of pathogens [8, 12]. In the context of oncology, VSIG4 is frequently overexpressed on M2-polarized TAMs, contributing to an immunosuppressive tumor microenvironment and poor patient prognosis in cancers such as non-small cell lung cancer, ovarian cancer, and multiple myeloma [9, 21, 35]. Therapeutic development focuses on anti-VSIG4 monoclonal antibodies, such as EU103 and VTX-1218, which are designed to block its inhibitory signals and repolarize TAMs from a pro-tumoral M2 phenotype to a pro-inflammatory M1 phenotype, thereby restoring anti-tumor immunity [37, 38, 40].

Other names

Complement receptor of the immunoglobulin superfamilyCRIgZ39IgB7-family-related proteinB7-related proteinZ39IG

Anti-VSIG4 monoclonal antibodies act as immune checkpoint inhibitors by blocking the interaction between VSIG4 and T cells, thereby restoring T-cell proliferation and cytokine production. Additionally, these drugs induce the repolarization of tumor-associated macrophages (TAMs) from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, enhancing the anti-tumor immune response [21, 22, 35].