Copper homeostasis and cuproptosis rewire the tumor microenvironment: mechanisms, immune modulation, and therapeutic...

Copper, an essential trace element with dual functions in cancer progression, drives tumor growth via oncogenic signaling, metabolic plasticity, and extracellular matrix remodeling. By contrast, copper overload triggers cuproptosis, a form of mitochondrial proteotoxic cell death mediated by the FDX1/LIPT1/DLAT/Fe-S regulatory axis. To date, a unified theoretical framework integrating copper metabolism, tumor microenvironment (TME) remodeling, and antitumor immunity remains lacking. In this review, we reframe the TME as a structured copper ecosystem in which both cellular components and the extracellular matrix are modulated by copper, and propose a contextual copper signaling network, in which copper-mediated tumor cell fate is determined by the labile copper pool, the metabolic state, and tumor cellular heterogeneity. We further delineate a unified causal chain linking cuproptosis-driven immunogenicity and cGAS-STING activation to immune cell activation and PD-L1 modulation. Therapeutically, copper chelation and cuproptosis induction strategies have demonstrated promising efficacy, and combining cuproptosis induction with existing antitumor therapies may reverse therapeutic resistance and enhance treatment efficacy. Future studies need to validate cuproptosis-related signatures as predictive biomarkers for precision oncology and refine copper-targeted therapies to minimize systemic toxicities.