A metallic metabolic nano-regulator reprograms the PKM2/HIF-1α/DLAT axis to amplify tumor-specific cuproptosis.

Abstract

Cuproptosis represents a novel form of mitochondria-dependent cell death, demonstrating a unique antitumor potential. However, tumor cells have evolved robust metabolic compensation mechanisms that mitigate the cytotoxic effects of copper ions; this barrier must be disrupted to trigger cuproptosis. In this study, a metallic metabolic nano-regulator (MC@BSA; MC, manganese-copper nanocomposite; BSA, bovine serum albumin) is designed, which efficiently accumulates in tumor tissues and disrupts copper homeostasis by inhibiting copper efflux and promoting the generation of reactive oxygen species (ROS). MC@BSA perturbs the copper ion equilibrium, leading to mitochondrial dysfunction, lipoylated protein aggregation, and ATP depletion. MC@BSA downregulates the PKM2/HIF-1α/DLAT signaling axis, effectively decoupling glycolysis from the mitochondrial metabolism and enhancing the cellular sensitivity to cuproptosis. The therapeutic potency of MC@BSA is augmented by the addition of a PKM2 activator (TEPP-46) to form an MC@BSA + TEPP-46 complex. TEPP-46 stabilizes PKM2 in its tetrameric form and inhibits its nuclear transcriptional functions, thereby intensifying metabolic disruption and oxidative stress, and amplifying the antitumor efficacy. In vivo experiments confirm that MC@BSA + TEPP-46 suppresses tumor growth without inducing significant systemic toxicity, highlighting its therapeutic safety and robust pharmacological profile. This strategy advances the understanding of copper-mediated cell death mechanisms and introduces a powerful avenue for metabolic intervention in cancer therapy.