In this study, we demonstrate that the combination of ICIs and MC1R-targeted α-particle TRT (α-TRT), using “click” cyclized α-MSH variant VMT01 radiolabeled with lead (Pb) isotope 212Pb to deliver α-particles, induce a cooperative anti-tumor effect in immunocompetent C57BL6 mice bearing syngeneic murine melanoma tumors (B16-F10), achieving a complete response rate of 43%. This evidence concerns the gene MC1R and neoplasm.