Glutathione Induced In Situ Activation of Dual‐Locked Cuproptosis Nanoamplifier with Glycolysis Metabolism Inhibition to Boost Cancer Immunotherapy

Abstract Interference with glycolysis metabolism not only promotes the efficient sensitization of cuproptosis, but also amplifies cytotoxic T cell functions and proliferations, thus contributing to relieve immunosuppressive tumor microenvironment. However, the synergistic mechanism and the design of multicomponent nanoformulations involving these three pathways have not yet been explored. a copper‐coordinated nanoassembly (designated as Cu‐GM) is reported here that integrates a lactate dehydrogenase inhibitor, galloflavin (GF), with an immune checkpoint inhibitor, myricetin (MY), to boost cancer cuproptosis‐immunotherapy. These results suggest that Cu‐GM can be activated by the endogenous overexpressed glutathione to release Cu + , leading to the abnormal aggregation of lipoylated proteins and iron‐sulfur cluster proteins loss, which triggers proteotoxic stress and cell cuproptosis. Meanwhile, the released GF not only inhibits the glycolysis to amplify cuproptosis efficacy but also achieves effective lactate depletion, thus alleviating immunosuppressive effects of lactate. Notably, the killed tumor cells can induce immunogenic cell death to evoke the anti‐tumor immunity, which further augmented by the MY‐mediated immune checkpoint blockade. Taken together, the first anticancer synergy of glycolysis metabolism, cuproptosis, and immunotherapy is presented, showcasing remarkable in vivo antitumor effects and encouraging further exploration of a rational multimodal treatment approach.