Hybrid Cell Membrane-Functionalized Nanoagents Synergistically Enhance Cuproptosis-Mediated Immunotherapy by Dual Modulation of Glycolytic Metabolism and Tumor Microenvironments.

Glycolytic activity of cancer cells not only reduces their vulnerability to cuproptosis but also heightens the immunosuppressive state of the tumor microenvironment (TME). Our study introduces a nanoplatform called dual-remodeling cuproptosis-inducing agent with hybrid cell membrane coating (DREAM), which is crafted to simultaneously modify the metabolic and immunological landscapes of the TME to enhance cuproptosis-driven immunotherapy. This platform exploits cancer-cell-derived membranes for homologous targeting, enhancing tumor specificity, intratumoral penetration, and intracellular copper delivery. DREAM's disruption of glycolysis intensifies the copper overload, triggering cuproptosis in cancer cells. Additionally, it alleviates immunosuppression and bolsters immune responses facilitated by the immunogenic cell death from cuproptosis, further potentiated by the immunostimulatory effect of M1 macrophage membranes. The outcome is a pronounced efficacy in curbing tumor growth and distant metastasis in squamous cell carcinoma and also in suppressing melanoma proliferation and lung metastasis. This research underscores the vital interaction among inhibiting glycolysis, enhancing sensitivity to cuproptosis, and activating immune responses, thereby paving a feasible and integrated pathway in cancer immunotherapy.