Thermal-triggered mitochondrial oxidative phosphorylation-enhanced nanodrug sensitizes cuproptosis with amplified anti-tumor immunity

Cuproptosis, a form of programmed cell death (PCD) dependent on mitochondrial respiration and driven by ferredoxin 1 (FDX1), has shown limited antitumor efficacy due to the Warburg effect. In order to break through this limitation, we first discover that cuproptosis is highly correlated with thermal stimulation because thermal stimulus is beneficial for improving tumor mitochondrial oxidative phosphorylation. On this basis, a thermal-responsive mitochondrial metabolism-regulable nanodrug (DIE) is developed by encapsulating two FDA-approved drugs, indocyanine green (ICG) and elesclomol (ES), into a dextran-based copolymeric nanocarrier. DIE is rich in disulfide bonds which are advantageous for depleting GSH and ensuring the cytotoxic Cu (I) concentrations required for cuproptosis. Upon near-infrared laser stimulation, DIE significantly sensitizes melanoma cells to cuproptosis through increasing mitochondrial reductase FDX1-mediated lipoylated protein aggregation and oxidative phosphorylation. Moreover, the enhanced cuproptosis further induces immunogenetic cell death and subsequently improves the efficacy of the PD-L1 immune checkpoint inhibitors, demonstrating excellent tumor suppression and metastasis inhibition. This study offers a novel approach to sensitize cancer cells to cuproptosis and provides a synergistic strategy for tumor immunotherapy.