Hypoxia‐Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

Abstract The immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia‐responsive delivery system is constructed simply by coordinating ferric (Fe 3+ ) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia‐sensitive dopamine derivative of polyethylene glycol (PEG) using “one‐pot” reaction for the “closed‐loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia‐sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate‐cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8 + T cells then release interferon γ (IFN‐ γ ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed‐loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor‐bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.