Copper (Cu) ions are essential for inducing cuproptosis to inhibit tumor growth, and the therapeutic efficacy is limited by the chelation of over-expressed glutathione (GSH) and the efflux mechanisms of copper transporter proteins. Moreover, the hypoxic characteristic of the tumor microenvironment (TME) can impede the formation of lipoylated proteins in the tricarboxylic acid (TCA) cycle, thereby diminishing cuproptosis. Herein, CuO was served as active nano-carrier for delivering copper, followed by coating with cerium-based node metal-organic frameworks (Ce-MOFs) in situ on the surface to form core-shell structure CuO@Ce-MOFs (CM). Subsequently, the small molecule glucose transporter (GLUT) inhibitor KL-11743 was loaded onto CM to construct CuO@Ce-MOFs/KL-11743 (CMK) nanocomposites, achieving efficient cuproptosis for tumor treatment. The results show that CMK regulated the redox metabolism of the tumor microenvironment (TME) through glutathione oxidase (GSHOx) and peroxidase (POD) activities, significantly consuming excessive GSH and preventing copper ions from being chelated. Furthermore, KL-11743 released in response to TME inhibited the transport of glucose into cells via GLUT, resulting in a reduction of ATP synthesis and down-regulation of ATP7B expression, thereby achieving the restriction of copper ion efflux by regulating energy metabolism. The catalase (CAT) activity of CMK catalyzed the overexpressed HOin TME to generate O, which entered the TCA cycle to promote lipoylated proteins oligomerization for sensitizing cuproptosis. In Summary, CMK nanocomposites increased the effective Cu ions concentration within tumor cells by regulating metabolism, resulting in toxicity stress by hypoxia reversion induced efficient cuproptosis, which provides a potential strategy for clinical tumor treatment. STATEMENT OF SIGNIFICANCE: This study addresses the challenge of insufficient effective copper ions and hypoxia in inhibiting cuproptosis by constructing TME-responsive Cu₂O@Ce-MOFs/KL-11743 (CMK) nanocomposites. In this design, CMK enhances intracellular copper retention through dual mechanisms: (1) redox metabolic regulation-mediated GSH depletion to inhibit copper ion chelation, and (2) KL-11743-targeted suppression of copper efflux via energy metabolic pathway inhibition. Concurrently, the enzyme-mimic activity of CMK catalyzes overexpressed H₂O₂ in the TME into O₂, alleviating hypoxia to promote lipoylated protein oligomerization. The synergistic integration of metabolic modulation and hypoxia reversal enables robust cuproptosis induction, establishing a reliable and clinically viable strategy for tumor treatment. 2 2 2 2 2 2
