Targeting copper metabolic homeostasis to enable cuproptosis-based cancer therapy

ABSTRACT: Cuproptosis, a recently defined form of programmed cell death, provides a new vantage point for cancer therapy. In tumor cells, copper (Cu) metabolic homeostasis is essential to satisfy heightened copper demands while preventing its toxicity. Disruption of this equilibrium, resulting in excessive intracellular copper accumulation, is a prerequisite for initiating cuproptosis. This review systematically synthesizes current knowledge on the dual roles of copper in tumorigenesis, progression, and therapeutic exploitation. It delineates the regulatory network governing copper metabolic homeostasis in cancer cells and summarizes the molecular mechanisms of cuproptosis. Furthermore, the discussion focuses on how disruption of this homeostasis triggers cuproptosis, highlighting key molecular pathways and druggable targets. Emerging therapeutic strategies leveraging copper biology in oncology are also examined. Collectively, targeting copper metabolic homeostasis represents a compelling approach for the advancement of cuproptosis-based tumor therapies, which hold substantial clinical promise.