VSIG2 as a novel immunosuppressive ligand interacts with Nectin-2 to regulate T cell responses.

Although B7 family immune checkpoint molecules such as PD-L1/PD-1 have improved the treatment of cancer and autoimmune diseases, more such molecules are still needed to expand therapeutic options. This study focuses on a novel molecule, VSIG2—previous studies suggested that VSIG2 acts as a receptor involved in T cell development, but this study is the first to identify a different mechanism of action, confirming that VSIG2 can function as an immunosuppressive ligand present on the surface of activated antigen-presenting cells. It specifically binds to Nectin-2 and does not interact with well-known immune receptors like PD-1 or CTLA-4; this binding strongly inhibits T cell activation and proliferation. In experiments, the human VSIG2-Ig protein alleviated the symptoms of experimental autoimmune encephalomyelitis, while anti-VSIG2 antibodies inhibited the growth of pancreatic cancer. The interaction between VSIG2 and Nectin-2 can regulate the STAT1/IRF1/GBP2 signaling pathway in T cells, thereby modulating T cell responses, and this axis is expected to serve as a novel therapeutic target for autoimmune diseases and cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03645-7.