Dynamically Reprograms Mitochondrial Respiration to Augment Cuproptosis in Cancer Therapy

ABSTRACT Cuproptosis, a newly identified form of regulated cell death, relies on copper ions and elevated mitochondrial respiration. This study elucidates the role of lactate oxidase in modulating cuproptosis by converting lactate to pyruvate, reprogramming energy metabolism, and thereby facilitating copper‐induced cell death. Here, this work develops a copper‐coordinated polymer for efficient delivery of lactate oxidase into cancer cells. The nanoparticles modulate the activities of pyruvate dehydrogenase and pyruvate kinase, and reshape the energy metabolism of tumor cells. This metabolic reprogramming initiates a boost in mitochondrial function that subsequently promotes cuproptosis through copper‐dependent dihydrolipoamide S‐acetyltransferase (DLAT) oligomerization and disruption of the tricarboxylic acid cycle. In addition to inducing cuproptosis, the nanoparticles also activate a noniron‐dependent Fenton‐like reaction, thereby promoting ferroptosis. The nanoparticles exhibit potent antitumor efficacy in vivo, underscoring the potential of exploiting metabolic vulnerabilities to enhance cuproptosis. This study introduces a novel therapeutic avenue that leverages metabolic reprogramming to initiate regulated cell death pathways in cancer treatment.