The study identifies leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a binding partner of V-domain immunoglobulin suppressor of T cell activation (VISTA), an immune checkpoint protein. LRIG1 acts as an inhibitory receptor by engaging VISTA, suppressing T cell responses. In mice, LRIG1 deletion in T cells leads to enhanced antitumor responses due to increased expansion and effector function of tumor-specific cytotoxic T lymphocytes (CTLs). In human melanoma tissues, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlates with resistance to immunotherapies. The findings suggest that targeting the VISTA/LRIG1 axis may be a promising approach for cancer immunotherapy.The study identifies leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) as a binding partner of V-domain immunoglobulin suppressor of T cell activation (VISTA), an immune checkpoint protein. LRIG1 acts as an inhibitory receptor by engaging VISTA, suppressing T cell responses. In mice, LRIG1 deletion in T cells leads to enhanced antitumor responses due to increased expansion and effector function of tumor-specific cytotoxic T lymphocytes (CTLs). In human melanoma tissues, elevated LRIG1 expression on tumor-infiltrating CD8+ CTLs correlates with resistance to immunotherapies. The findings suggest that targeting the VISTA/LRIG1 axis may be a promising approach for cancer immunotherapy.