Copper-EGCG nanoreactor orchestrates dual-metabolic assault and self-amplified cuproptosis for immunogenic prostate cancer therapy

Prostate cancer (PCa) is characterized by a unique metabolic dependency on the hyperactivated tricarboxylic acid (TCA) cycle, creating a distinct vulnerability to cuproptosis—a copper-dependent form of regulated cell death. However, metabolic plasticity allows tumor cells to evade single-pathway inhibition through compensatory glycolysis, limiting the efficacy of copper-based therapies. Therefore, there is an urgent need to develop integrated nanoplatforms capable of orchestrating a dual-pathway metabolic blockade to overcome this therapeutic resistance. Herein, we engineered a self-assembling copper-epigallocatechin gallate (EGCG) nanoreactor (Cu-EQ NP) designed to execute a synchronized dual-metabolic assault. The Cu-EQ NPs leverage the tumor microenvironment to release copper ions that trigger TCA-dependent cuproptosis, while the EGCG component simultaneously inhibits key glycolytic enzymes to prevent metabolic escape. Mechanistically, this lethality is self-amplified by EGCG-quinone-mediated depletion of glutathione (GSH) and the downregulation of the ATPase copper-transporting beta (ATP7B) efflux pump, leading to irreversible intracellular copper accumulation. Furthermore, we demonstrate that this metabolic collapse is highly immunogenic. In a syngeneic RM-1 mouse model, Cu-EQ NP-induced immunogenic cell death (ICD) released damage-associated molecular patterns (DAMPs) that successfully transformed the immunologically “cold” tumor microenvironment. This remodeling was characterized by enhanced dendritic cell maturation, M2-to-M1 macrophage repolarization, and robust infiltration of cytotoxic CD8 + T cells, resulting in potent tumor regression. The Cu-EQ nanoreactor represents a precision nanomedicine strategy that converts the specific metabolic vulnerabilities of PCa into a fatal weakness. By integrating dual-metabolic disruption with robust immune activation, this platform offers a promising therapeutic paradigm for overcoming resistance in advanced prostate cancer.