Modifying metabolic and immune hallmarks of cancer by a copper complex

Metabolic adaptation of cancer cells is a key tactic for maintaining their tumorigenicity and viability in the tumor immune microenvironment (TIME). Concurrent modulation on the metabolic pathway and immune system could change the living condition of cancer cells and potentiate the efficacy of anticancer drugs. A copper complex (DDCu) was designed to influence the energy metabolism of cancer cells and reshape the TIME. DDCu restrained the production and transportation of lactate by inhibiting the expression of lactate dehydrogenase and monocarboxylate transporter 4, thereby altering the metabolic pathway of cancer cells and improving the acidic tumor microenvironment. Meantime, DDCu was reduced to Cu⁺ by cellular glutathione to react with lipoylated proteins of the tricarboxylic acid cycle and destabilize the Fe–S cluster proteins, leading to the aggregation of dihydrolipoamide S-acetyltransferase and cuproptosis in cancer cells. Furthermore, DDCu promoted the polarization of macrophages from the M2 to M1 phenotype, activated CD4⁺ and CD8⁺ T cells, and reversed the immunosuppression. As a result, DDCu inhibited the tumor growth through a synergy between metabolic regulation and immunomodulation.