A Metabolic NanoLock Strategy Enhances Cuproptosis in Hypoxic Tumors by Enforcing Mitochondrial Respiration and Suppressing Glycolysis.

Abstract

As a promising challenging anti-cancer strategy, cuproptosis is limited by the metabolic adaptations of solid tumors. That is, tumor hypoxia inhibits mitochondrial respiration, while compensatory hyperactive glycolysis contributes to metabolic escape. For overcoming this dual resistance, a Metabolic NanoLock strategy was proposed in this study, that is a photothermal-chemical dual-mode oxygen-generating nanosystem (PCFI) to achieve lethal metabolic reprogramming. Upon activation in the tumor microenvironment, the released Cu⁺ catalyse H₂O₂ to generate O₂ through Fenton-like reaction. Concurrently, the thermal effect induced by ICG under 808 nm laser irradiation promotes O₂ release from oxygen-loaded perfluorocarbon, ensuring sustained oxygen supply. This dual action restores mitochondrial electron transport chain activity while enhancing tricarboxylic acid cycle engagement, compelling tumor cells to rely on respiratory metabolism. Meanwhile, the ROS storm induced by copper and ICG suppresses pyruvate kinase activity, blocking the glycolytic pathway and eliminating the Warburg effect compensation mechanism. Tumor cells were forced into a non-adaptive metabolic state that cannot sustain glycolysis or mitochondrial compensation, effectively trapped in a designed metabolic cage, thereby amplifying cuproptosis sensitivity. In addition to directly inducing metabolic collapse, this locked metabolic state also promotes immunogenic cell death, driving downstream antitumor immune activation. This study establishes metabolic locking as a universal strategy to overcome cuproptosis metabolic resistance, providing a conceptually unique framework for leveraging tumor metabolic vulnerability to achieve durable anticancer efficacy. STATEMENT OF SIGNIFICANCE: Solid tumors often develop metabolic resistance by shifting their energy pathways under hypoxic conditions, favoring glycolysis over mitochondrial respiration. This metabolic adaptation significantly diminishes the efficacy of cuproptosis, a recently identified copper-dependent cell death pathway. In this work, we constructed a multifunctional nanoplatform (PCFI) utilizing a "Metabolic NanoLock" strategy to overcome this therapeutic barrier. The system promotes mitochondrial respiration through in situ oxygen generation and simultaneously inhibits glycolytic escape via ROS-mediated enzyme suppression. By effectively locking tumor cells into a respiration-dependent state, the platform markedly sensitizes tumors to cuproptosis under both normoxic and hypoxic conditions. This study provides a rational metabolic-regulation design for biomaterials and offers a promising strategy for enhancing copper-mediated cancer therapy.