Hijacking Endogenous Iron and GSH Via a Polyvalent Ferroptosis Agonist to Enhance Tumor Immunotherapy

Abstract The clinical application of ferroptosis, characterized by iron‐dependent lipid peroxidation, is limited because of the serious side effects of using toxic‐dose iron. Herein, a polyvalent ferroptosis agonist‐a hypoxia responsive polymer bearing 18‐crown‐6 ring (hPPAA18C6) is developed. In contrast to the natural ferroptosis agonists (erastin, RSL3, and sorafenib), hPPAA18C6 stimulates the ferroptosis by releasing endogenous iron stored in the natural “iron pools” of cellular organelles and depleting glutathione (GSH) via the benzoquinone generated from the cascade decaging reactions in hypoxia. hPPAA18C6 nanoparticle is loaded with photosensitizer‐chlorine e6 (Ce6) (hPPAA18C6@Ce6) due to the inhomogeneous hypoxia microenvironment. Moreover, the exposed positively charged primary amine (NH 2 ) from hPPAA18C6 acts as an immune adjuvant, facilitating dendritic cells maturation, antigen presentation, and cytotoxic T lymphocyte activation. hPPAA18C6@Ce6 induces anti‐tumor responses that are dependent on ferroptosis, photodynamics therapy (PDT), and CD8 + T‐cell activity. In addition, the combination of hPPAA18C6 and Ce6 leads to combined therapeutic outcomes in primary, distant, and metastatic tumors. The activation of the ferroptosis pathway through functional polymer‐hijacking endogenous iron and GSH may offer new therapeutic opportunities.