Engineered Iron-Based nanoplatform amplifies repolarization of M2-Like Tumor-Associated Macrophages for enhanced cancer immunotherapy

•Dic@M2pep-Fe-MOF enhances the intracellular iron accumulation in M2-like TAMs.•Dic@M2pep-Fe-MOF efficiently improves M2-to-M1 TAM repolarization.•Dic@M2pep-Fe-MOF-repolarized M2-like TAMs kill and phagocytose tumor cells.•Dic@M2pep-Fe-MOF remodels tumor immune microenvironment. Resetting M2-like tumor-associated macrophages (TAMs) to antitumor M1 phenotype is a promising strategy in cancer immunotherapy. Although iron-based nanoparticles exhibit the potential of M2-to-M1 macrophage repolarization, the efficient M2-like TAM targeting and the subsequent intracellular iron retention remains a big challenge. Here, M2 macrophage-targeting peptide-conjugated iron-based metal–organic frameworks are developed to load diclofenac (Dic@M2pep-Fe-MOF) for enhanced cancer immunotherapy. Dic@M2pep-Fe-MOF efficiently targets M2-like TAMs and decreases the efflux by hepcidin/ferroportin signaling pathway, enabling enhanced intracellular accumulation for improved M2-to-M1 macrophage repolarization. Dic@M2pep-Fe-MOF-repolarized M2-like TAMs efficiently kill and phagocytose tumor cells, and importantly remodel tumor immune microenvironment to generate long-term antitumor immune memory, eliciting strong anticancer efficacy with tumor recurrence inhibition. Our results support Dic@M2pep-Fe-MOF as a potential drug for cancer immunotherapy.