Metal-phenolic networks reverse the immunosuppressive tumor microenvironment via dual metabolism regulation and immunogenic cell death

Targeting cancer cell metabolism has emerged as a promising strategy to reverse the immunosuppressive tumor microenvironment (TME). Aerobic glycolysis, the dominant metabolic pathway in cancer cells, leads to glucose depletion and the accumulation of immunosuppressive metabolites such as lactate, ultimately limiting the efficacy of conventional immunotherapies. In this study, metal phenolic-networks (MPNs) are developed by coating zinc oxide (ZnO) nanoparticles with epigallocatechin gallate (EGCG) to modulate cancer metabolism for TME reprogramming and immune activation. Under acidic conditions, MPNs release Zn²⁺ ions and EGCG, inhibiting both glycolysis and mitochondrial metabolism, effectively regulating the metabolic ability of cancer cells. Furthermore, severe starvation stress induced by dual metabolic inhibition triggers immunogenic cell death (ICD) without the need for conventional ICD inducers. Consequently, MPN treatment reverses the immunosuppressive TME through dual metabolic regulation and ICD, which induces dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression. These findings highlight the potential of combining metabolic therapy with immunotherapy as a novel strategy to enhance antitumor immunity and overcome the limitations of current cancer treatments.