Roles and mechanisms of cuproptosis for reversing cancer therapeutic resistance.

Cancer therapeutic resistance remains a major obstacle in clinical oncology, driven by multifaceted mechanisms including multidrug resistance, radioresistance, and immune evasion. Recent advances highlight cuproptosis, a novel copper-dependent programmed cell death modality, as a promising strategy to overcome these challenges. Cuproptosis is triggered by mitochondrial copper overload, leading to lipoylated protein aggregation, tricarboxylic acid cycle disruption, and proteotoxic stress. The regulatory mechanism of copper ions and cuproptosis on cancer offers a unique vulnerability for targeting therapy-resistant malignancies. This review summarized the mechanisms of copper ions, the discovery of cuproptosis, the commonly used copper ionophores and the potential of cuproptosis in overcoming therapeutic resistance, as well as the remaining challenges and future directions concerning cuproptosis. It will provide a novel therapeutic paradigm to overcome cancer therapeutic resistance.