Multi‐Hierarchical Fe Single Atom Nanozymes with Axially‐Coordinated O‐Fe‐N₄ Active Centers Reshape Macrophage Epigenetics Against Immunosuppression

Abstract Immunosuppression is ubiquitous in solid tumors, characterized by few cytotoxic T infiltrations, abundant inflammation enrichment, immunosuppressive cell recruitment, etc., which is especially potentiated by incomplete tumor resection. In this report, multi‐hierarchical Fe single‐atom nanozymes (SAzymes) featuring axially‐coordinated O‐Fe‐N₄ active centers are constructed to reshape tumor‐associated macrophages (TAMs) epigenetics via repolarizing their phenotypes, which is highly profitable for mitigating tumor immunosuppression after incomplete radiofrequency ablation (iRFA). Therein, a nitrogen‐doped bamboo‐like carbon nanotube (N‐BCNT) is engineered to coordinatively immobilize Fe atoms, wherein another axial coordination (O) is introduced to further switch non‐polar Fe‐N₄ to polar O‐Fe‐N₄. The polarization switching of active centers synergies with N doping‐encouraged electron transport, low‐temperature synthesis‐discouraged N loss and large surface area‐unlocked O‐Fe‐N₄ enrichment to confer tetra‐enzymic catalysis activities including peroxidase, oxidase, catalase, and glutathione oxidase, maximumly favoring reactive oxygen species (ROS) production and hypoxia reversal. After delivering TAMs polarization‐encouraged drug, toosendanin, TAMs epigenetics are altered and their phenotypes are repolarized to relieve immunosuppression and magnify immune responses, which suppress residual tumor progression after iRFA. Such a comprehensive structure optimization strategy provides a versatile route to design and construct SAzymes‐like drugs with multi‐enzymatical catalysis activities.