The first axis—peptide 4S5NG-PE24—selectively targets integrin α6+ melanoma cells, inducing pyroptosis via caspase-3/GSDME activation and enhancing anti–PD-1 immunotherapy offers tumor-specific cytotoxicity, minimal off-target toxicity, and immunogenic cell death—a rare trifecta in targeted cancer therapy. Here, CASP3 is linked to melanoma.