Nilotinib induces immunogenic cuproptosis to potentiate cancer immunotherapy

Summary: Immunotherapy efficacy is limited by poor tumor immunogenicity and insufficient immune infiltration, highlighting the critical role of inducing immunogenic cell death for improved outcomes. Targeting cuproptosis holds promising therapeutic potential, but its immunogenic and capacity to stimulate anti-tumor immunity to potentiate immunotherapy remains unknown. Through screening of 240 Food and Drug Administration (FDA)-approved anti-tumor drugs, we identify nilotinib as a potent cuproptosis inducer in cancer cells, especially at physiologically relevant copper concentrations. Mechanistically, nilotinib-copper elicits cuproptosis in vitro and in vivo by repressing the copper exporter ATP7A via ETV1 to drive mitochondrial copper accumulation and activating mitogen-activated protein kinase (MAPK) pathway through ERK2 phosphorylation. Preclinically, nilotinib-copper induces immunogenic cuproptosis and enhances anti-PD-1 efficacy across multiple melanoma models, including B16F10 tumor-bearing mice, Braf/Pten-driven spontaneous melanoma mice, and PBMC-humanized mice. Clinically, the ATP7ALow/MAPKHigh signature correlates with improved immunotherapy response and prolonged overall survival. This work establishes nilotinib as a clinically tractable, non-ionophore immunogenic cuproptosis inducer capable of activating anti-tumor immunity to potentiate immunotherapy.