Cuproptosis-based nanomedicine targeting metabolic vulnerabilities for cancer therapy

Cancer remains the leading cause of mortality worldwide, with metastatic disease accounting for the majority of cancer-related deaths. Despite advances in conventional therapies, the outcome for patients with advanced malignancies remains poor due to tumor heterogeneity and therapy resistance. Cuproptosis, a copper-dependent regulated cell death pathway, is characterized by mitochondrial aggregation of lipoylated tricarboxylic acid cycle proteins and depletion of iron-sulfur cluster proteins, causing proteotoxic stress and cell death. Cuproptosis is linked to cellular metabolism, particularly glucose and lipid metabolism, suggesting that cancer cells with distinct metabolic profiles exhibit differential sensitivity to cuproptosis induction. Nanomedicine-based approaches have advanced the delivery of copper-based therapeutics, enabling controlled release, enhanced tumor targeting, and tumor microenvironment-responsive activation. This review delineates the molecular mechanisms of cuproptosis with emphasis on its metabolic underpinnings, summarizes recent nanomedicine strategies that exploit metabolic vulnerabilities for cancer therapy, and discusses the crosstalk between cuproptosis and other cell death pathways through shared metabolic nodes. Translational challenges, biosafety issues, and future directions such as AI-driven design and organoid-based models are also addressed, aiming to provide a comprehensive framework for leveraging cuproptosis-based nanomedicine in precision cancer therapy. Literature was retrieved from PubMed, Web of Science, and Scopus, covering publications up to June 2026.