Peptide Coacervates with Metal–Phenolic Membranes Modulate Glucose Metabolism and Enhance Cancer Immunotherapy

Abstract Glucose consumption by tumors induces metabolic restriction of T cells, which results in immune evasion and tumor progression. Regulating cellular metabolism represents a promising strategy to enhance cancer immunotherapy; however, redirecting glucose utilization from tumor cells to T cells is challenging. Herein, the activation of cytotoxic T cells using engineered peptide coacervates (PCs) containing interferon alpha (IFNα) and membranized with metal–phenolic networks (MPNs) (PC‐IFNα@MPNs), which promote glucose uptake and glycolysis, is reported. PC‐IFNα@MPNs modulate the molecular conformation of the co‐stimulatory lymphocyte function‐associated antigen 1 on CD8 + T cells, while suppressing tumor cell glycolysis through the sustained release of IFNα, thereby increasing the energy supply for T cells. Furthermore, PC‐IFNα@MPNs suppress tumor progression in preclinical orthotopic tumor mouse models by facilitating T cell infiltration and activation. When combined with immune checkpoint blockade (ICB), PC‐IFNα@MPNs further improve therapeutic outcomes (99% inhibition of tumor growth), even in ICB‐insensitive tumor models. Notably, PC‐IFNα@MPNs exert a robust immune‐memory effect (a 4.8‐fold increase in memory T cells) and provide long‐lasting anti‐tumor activity (over 74 days), thereby preventing postsurgical tumor recurrence. The present study offers insights into metabolic intervention mechanisms mediated by glucose modulation and provides a rational design for metal–organic materials in cancer therapy.