Cuproptosis in glioma: mechanistic insights, metabolic vulnerabilities, and emerging translational opportunities

Gliomas, particularly glioblastoma (GBM), remain refractory to current therapies because of metabolic plasticity, immune suppression and resistance to apoptosis. Although several programmed cell death pathways have been investigated, therapeutic resistance remains a major barrier. Cuproptosis, a copper-dependent mitochondrial cell death mechanism that targets lipoylated tricarboxylic acid (TCA) cycle proteins, exposes a metabolically selective vulnerability. This review summarizes recent mechanistic advances in cuproptosis, integrates cuproptosis-related gene (CRG) signatures with glioma heterogeneity under the 2021 WHO molecular classification framework, and evaluates nanotechnology-based copper delivery systems designed to overcome the blood-brain barrier (BBB). By examining cuproptosis in tumor metabolic rewiring and immune modulation, we highlight its potential as a therapeutic axis in glioma. Compared with previous reviews that summarized broader cancer or glioma-related mechanisms without molecular subtype stratification, this review emphasizes three features: cuproptosis characteristics across WHO-defined glioma subtypes, BBB penetration challenges and nanomedicine delivery strategies, and clinical translational barriers for copper-targeted therapies. Despite promising preclinical evidence, the clinical efficacy of cuproptosis-targeted therapy remains unproven, and rigorous glioma-specific validation is required.