Metabolic Inhibitor Loaded Metal-Phenolic Nanocapsules Enable Synergistic Cancer Therapy through Cuproptosis and Immunometabolic Reprogramming.

Abnormal glycolysis and glutamine metabolism not only sustain tumor growth but also reprogram the tumor microenvironment (TME). However, due to compensatory mechanisms and low tumor immunogenicity, targeting a single metabolic pathway is often insufficient for effective cancer therapy. We here developed dual-starvation therapeutic metal-phenolic nanocapsules (CG@Cap) by encapsulating a glutamine metabolism inhibitor with a zeolitic imidazolate framework-8 and adsorbing glucose oxidase on the surface, followed by coordination-driven assembly with tannic acid and copper ions. After preferential accumulation at tumor sites and internalization by tumor cells, the nanocapsules release their cargo, simultaneously suppressing glycolysis and glutamine metabolism. This dual inhibition disrupts tumor energy supply and remodels the immunosuppressive TME. Furthermore, the resulting redox imbalance enhances copper-induced cuproptosis, eliciting a strong antitumor immune response. In tumor-bearing mice, CG@Cap demonstrated potent therapeutic efficacy, highlighting the promise of integrating immunometabolic reprogramming with cuproptosis induction for cancer therapy.