Biomimetic inducer enabled dual ferroptosis of tumor and M2-type macrophages for enhanced tumor immunotherapy

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment which promotes the formation of the immunosuppressive tumor microenvironment (ITME) through multiple mechanisms, severely counteracting the therapeutic efficacy of immunotherapy. In this study, a novel biomimetic ferroptosis inducer (D@FMN-M) capable of ITME regulation for enhanced cancer ferroptosis immunotherapy is reported. Upon tumor accumulation of D@FMN-M, the intratumoral mild acidity triggers the biodegradation of Fe-enriched nanocarriers and the concurrent co-releases of dihydroartemisinin (DHA) and Fe³⁺. The released Fe³⁺ is reduced to Fe²⁺ by consuming intratumoral glutathione (GSH), which promotes abundant free radical generation via triggering Fenton and Fe²⁺-DHA reactions, thus inducing ferroptosis of both cancer cells and M2-type TAMs. Resultantly, the anticancer immune response is strongly activated by the massive tumor-associated antigens released by ferroptositic cancer cells. Also importantly, the ferroptosis-sensitive M2-type TAMs will be either damaged or gradually domesticated to ferroptosis-resistant M1 TAMs under the ferroptosis stress, favoring the normalization of ITME and finally amplifying cancer ferroptosis immunotherapeutic efficacy. This work provides a novel strategy for ferroptosis immunotherapy of solid tumors featuring TAMs infiltration and immunosuppression by inducing dual ferroptosis of tumor cells and M2-type TAMs.