Bimetallic Nanozyme Amplifier for Synergistic Ferroptosis-Cuproptosis and Metabolic Reprogramming to Reshape Immunosuppressive Tumor Microenvironment.

Although ferroptosis and cuproptosis have shown potential in tumor therapy, their anti-tumor efficacy remains considerably limited due to aberrant metabolism within tumor cells and the immunosuppressive tumor microenvironment (TME). Herein, metal-organic framework nanoparticles (PEG@AuCZ@CC) are engineered by incorporating Au nanoparticles and α-Cyano-4-hydroxycinnamic acid (CHCA), to maximize hydrogen peroxide production and induce metabolic shift from aerobic glycolysis to oxidative phosphorylation in tumor cells. Interestingly, metabolic reprogramming of tumor cells not only enhances both ferroptotic and cuproptotic signaling cascades, amplifies immunogenic cell death (ICD) effects, but also reduces intratumoral glucose consumption and extracellular lactate accumulation, thereby creating a glucose-enriched but lactate-depleted TME. Consequently, the platform significantly promotes dendritic cells maturation, enables epigenetic reprogramming of tumor-associated macrophages (TAMs), and restores CD4⁺/CD8⁺ T-cells functionality. This multimodal strategy reshapes the tumor microenvironment (TME) by integrating cell death modulation and cell metabolism regulation, effectively overcoming immune tolerance, presenting a promising paradigm for hepatocellular carcinoma (HCC) therapy.