Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Abstract The induction of cuproptosis, a recently identified form of copper‐dependent immunogenic cell death, is a promising approach for antitumor therapy. However, sufficient accumulation of intracellular copper ions (Cu 2+ ) in tumor cells is essential for inducing cuproptosis. Herein, an intelligent cuproptosis‐inducing nanosystem is constructed by encapsulating copper oxide (CuO) nanoparticles with the copper ionophore elesclomol (ES). After uptake by tumor cells, ES@CuO is degraded to release Cu 2+ and ES to synergistically trigger cuproptosis, thereby significantly inhibiting the tumor growth of murine B16 melanoma cells. Moreover, ES@CuO further promoted cuproptosis‐mediated immune responses and reprogrammed the immunosuppressive tumor microenvironment by increasing the number of tumor‐infiltrating lymphocytes and secreted inflammatory cytokines. Additionally, combining ES@CuO with programmed cell death‐1 (PD‐1) immunotherapy substantially increased the antitumor efficacy in murine melanoma. Overall, the findings of this study can lead to the use of a novel strategy for cuproptosis‐mediated antitumor therapy, which may enhance the efficacy of immune checkpoint inhibitor therapy.