Emerging mechanistic insights into cuproptosis in cancer: Metabolic rewiring and therapeutic targeting

Copper, an essential trace element, has recently garnered significant attention in oncology because of cuproptosis, a novel regulated cell death mechanism driven by copper accumulation and its interactions with critical metabolic enzymes. This unique form of cell death is distinct from other established programmed cell death pathways and has profound implications for cancer therapies. Although cuproptosis holds immense therapeutic promise, a comprehensive understanding of its intricate mechanisms, interplay with cellular metabolism, and associated challenges in clinical translation remains to be elucidated. This review systematically details the mechanisms of cuproptosis, its complex interplay with cellular metabolism, and its emerging role in tumorigenesis and therapeutic intervention. We further explored innovative strategies developed to harness cuproptosis, including copper ionophores, nanoparticle delivery systems, small molecules, and gene modulation. Ultimately, we critically examine the existing challenges and future directions in translating cuproptosis-targeting strategies from preclinical models to clinical applications, emphasizing the need for a balanced approach to exploit the dual effects of copper in cancer progression.