Copper-enriched zinc peroxides induced cuproptosis through concurrent metabolic and oxidative dysregulation for boosting immunotherapy in colorectal cancer

Despite the immunotherapy has achieved the progress for advanced colorectal cancer, the unsatisfactory treatment effect remains a challenge due to the deficient immune response. In this work, we constructed a tumor microenvironments (TME)-responsive biodegradable cuproptosis inducer (ZnO₂-Cu@HA, ZCH) through cation-exchange method for amplifying the immune response. Compared to free copper ions, ZCH cloud achieve the controllable release of Cu²⁺ in tumor site, trggering efficient cuproptosis but reducing the side effect of normal tissues. Furthermore, the released Zn²⁺ could also inhibit intracellular glycolysis and ATP generation, then block the ATP7B to reduce the efflux of copper ions. Meanwhile, ZCH broke intracellular redox homeostasis via the release of exogenous H₂O₂, Cu⁺-mediated Fenton-like reaction and Zn²⁺-induced endogenous mitoROS, amplifying the cuproptosis to inducing immunogenic cell death (ICD) triggered for highly efficient immunotherapy of colorectal cancer. These findings demonstrated that it is a promising strategy of inducing efficient cuproptosis by the synergistic effect of accumulation of copper ions, inhibiting glycolysis and down-regulation GSH for efficient immunotherapy of colorectal cancer.