VSIR (V-domain immunoglobulin suppressor of T cell activation) is an immunoregulatory receptor that functions as an inhibitory immune checkpoint molecule. Mechanistically, VSIR suppresses T cell activation and proliferation by binding to LRIG1 on T cells and intestinal stem cells, thereby inhibiting T cell receptor signaling 1. VSIR also engages with macrophage-derived pathways to suppress epithelial repair through PPARα inhibition in intestinal stem cells 2. Additionally, VSIR promotes regulatory T cell differentiation while negatively regulating pro-inflammatory cytokine production including TNF, IL-17, and IFN-γ 3. In disease contexts, VSIR expression is significantly elevated in acute myeloid leukemia (AML) and predicts poor patient survival, with higher expression correlating with disease progression from myelodysplastic syndromes 4. In tumor immunity, TIM3+VISTA+ tumor-associated macrophages maintain an anti-inflammatory, immunosuppressive phenotype that resists immunotherapy, and targeting this axis synergizes with immunogenic cell death-inducing chemotherapy 5. VSIR-deficient mice develop exacerbated psoriasis-like inflammation with altered macrophage and dendritic cell populations 6, while VSIR blockade ameliorates DSS-induced colitis severity 2. These findings position VSIR as a critical immune checkpoint with therapeutic potential in cancer immunotherapy and inflammatory bowel disease.