Tackling cuproptosis: from metabolic rewiring to therapeutic exploitation in cancer.

Cuproptosis, a recently identified copper-dependent form of regulated cell death, is driven by mitochondrial dysfunction caused by copper overload. Cuproptosis results from proteotoxic stress, which is triggered by copper-induced aggregation of lipoylated tricarboxylic acid (TCA) cycle enzymes and destabilization of iron-sulfur cluster proteins. This review elucidates the mechanisms of cuproptosis, emphasizing its regulation by copper homeostasis, metabolic reprogramming, and key signaling pathways such as p53, HIF-1α, Wnt/β-catenin, and AKT. Notably, copper modulates antitumor immunity through its effects on the tumor microenvironment, suggesting a critical role in cancer immunotherapy. Therapeutic strategies using copper ionophores and nanomedicine platforms demonstrate potential to induce cuproptosis in a variety of cancers. Preclinical studies highlight cuproptosis as a promising strategy against malignancies with copper dysregulation or mitochondrial metabolism adaptation, while clinical translation requires biomarker-driven patient stratification and optimized delivery systems. This synthesis provides a framework for harnessing cuproptosis in precision oncology, bridging mechanistic insights to therapeutic innovation.