Cuproptosis in cancer: emerging mechanism and therapeutic opportunities

Cuproptosis is a mitochondria- and copper-dependent regulated form of cell death that has attracted growing interest as a therapeutic strategy in oncology. Its core mechanism involves the aggregation of lipoylated proteins in the tricarboxylic acid cycle to trigger proteotoxic stress and the destabilization of iron-sulfur cluster proteins, leading to mitochondrial dysfunction. These two effects synergize to initiate this regulated form of cell death. Recent studies have expanded this framework, revealing multilayered regulation through the core proteins of cuproptosis, mitochondrial respiratory function, and cellular copper homeostasis. Translational efforts have led to the development of copper-based therapeutics, including ionophores and nanomaterials. The utilization of smart-responsive nanomaterials also offers improved precision in tumor delivery and resistance circumvention. Here, we provide an updated overview of the mechanisms and regulation of cuproptosis and critically evaluate therapeutic strategies targeting it for cancer treatment.