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 (ZnO 2 -Cu@HA, ZCH) through cation-exchange method for amplifying the immune response. Compared to free copper ions, ZCH cloud achieve the controllable release of Cu 2+ in tumor site, trggering efficient cuproptosis but reducing the side effect of normal tissues. Furthermore, the released Zn 2+ 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 H 2 O 2 , Cu + -mediated Fenton-like reaction and Zn 2+ -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. A novel TME-responsive biodegradable nanoplatform (ZnO 2 -Cu@HA, ZCH) was constructed by doping copper ions through cation-exchange method before functionalized with hyaluronic acid (HA) for inducing the efficient antitumor immune response mediated by cuproptosis. The nanoplatform inducing cuproptosis by accumulation of copper ions, inhibiting glycolysis and down-regulation GSH has a promising potential to induce immune response for boosting colorectal cancer immunotherapy.