Roles of cuproptosis in central nervous system tumors: from molecular mechanisms to therapeutic prospects

Cuproptosis is a form of programmed cell death reported in 2022, characterized by copper ions directly binding to mitochondrial lipoylated proteins, inducing aberrant protein aggregation and destabilizing iron-sulfur cluster proteins, ultimately leading to cell death. Distinct from apoptosis, ferroptosis, and other known death modalities, cuproptosis does not rely on classical caspase pathways but exerts its cytotoxic effects by interfering with mitochondrial metabolism. Copper, an essential trace element for humans, maintains its homeostasis through precise regulation by transporters such as CTR1 (copper transporter 1), ATP7A (ATPase copper transporting alpha), and ATP7B (ATPase copper transporting beta). Dysregulated copper metabolism is closely associated with tumor initiation and progression. The central nervous system, being one of the organs with the highest copper content, exhibits heightened sensitivity to copper homeostasis imbalance. During metabolic reprogramming, central nervous system tumors such as glioma and medulloblastoma display enhanced copper dependency, rendering them potential targets for cuproptosis-inducing agents. However, tumor cells can develop resistance to cuproptosis through multiple mechanisms, including upregulation of ATP7A/ATP7B to promote copper efflux, downregulation of FDX1 (ferredoxin 1) and DLAT (dihydrolipoamide S-acetyltransferase) to reduce molecular sensitivity, activation of antioxidant systems such as glutathione, and metabolic switching toward glycolysis. Although several reviews have summarized cuproptosis mechanisms, a comprehensive synthesis focusing specifically on central nervous system tumors remains lacking. This review aimed to systematically examine the molecular basis of copper metabolism and cuproptosis, research progress in various central nervous system tumors, resistance mechanisms and counterstrategies, and cuproptosis-targeted therapeutic approaches. By bridging mechanistic insights with translational challenges unique to neuro-oncology, this review aimed to provide a theoretical foundation for the clinical application of cuproptosis-based therapies and to guide future research directions. Current evidence demonstrates that copper ionophores such as elesclomol and disulfiram, copper-based nanomaterials, and combination strategies with immunotherapy or radiotherapy exhibit promising antitumor efficacy in central nervous system tumor models. Meanwhile, challenges including blood-brain barrier delivery efficiency, normal neuron protection, and elucidation of resistance mechanisms remain major hurdles for clinical translation. The findings of this review could provide a theoretical foundation for the translational application of cuproptosis in neuro-oncology and guide future research directions.