VSIG3, also known as IGSF11, BT-IgSF, and CLMP, is a homophilic adhesion molecule that preferentially expressed in the brain. The function of VSIG3 is to stimulate cell growth through homophilic interactions. In clinical, the VSIG3 has been reported to as a novel target for cancer immunotherapy of gastrointestinal and hepatocellular carcinomas. In addition, VSIG-3 is also a ligand of B7 family member VISTA/PD-1H and inhibits human T-cell functions through a novel VSIG-3/VISTA pathway. VSIG-3/VISTA co-inhibitory pathway may provide new strategies for the treatment of human cancers and autoimmune disorders.