Disrupting intracellular redox homeostasis through copper-driven dual cell death to induce anti-tumor immunotherapy.

Abstract

The abnormality of redox homeostasis within tumors serves as a fundamental driving force for their growth and metastasis. Based on the coordination chemistry of specific metal ions, the precise modulation of intracellular reduction mechanisms by blocking key enzyme activities is expected to become an emerging anti-tumor strategy. Here, we developed a copper-based nanoinducer (CST NPs) that simultaneously induces both cuproptosis and disulfidptosis by disrupting intracellular copper ion homeostasis. In the acidic tumor microenvironment (TME), CST NPs can inhibit glucose-6-phosphate dehydrogenase (G6PD) activity, thereby reducing NADPH production, decreasing cysteine conversion, and significantly depleting the substrate required for glutathione (GSH) synthesis. Subsequently, a substantial amount of reactive oxygen species (ROS) can be generated through the cascade catalysis of copper ions contained in CST NPs. Concurrently, the cellular redox homeostasis is further disrupted with the widespread depletion of GSH by Cu²⁺. In addition, CST NPs have been demonstrated to directly induce cytoskeletal contraction and rupture, resulting in membrane disruption and the subsequent exposure and release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). This process initiates a potent immune response by reprogramming the immunosuppressive TME. This work presents a novel paradigm that precisely regulates intracellular copper ion homeostasis to induce both cuproptosis and disulfidptosis, offering a new theoretical basis for further elucidating the potential mechanisms of copper-induced cell death.