Ferritin Nanocomplex-Empowered “Three Birds with One Stone” Strategy for Cancer Immunotherapy

Strategies focusing on dually targeting tumor cells and immune cells within the immunosuppressive tumor microenvironment (TME) hold promising potential for improving the efficacy of cancer immunotherapy; however, they are challenging due to the off-target adverse effects of the nonselective killing effect on tumor cells and immune cells. Herein, a ferritin-albumin nanocomplex (IL@FA NPs) encapsulated with the photosensitizer IR820 and lipoic acid (LA) is designed to selectively reinforce the ferroptosis-induced tumor cell death, promote DC activation and tumor-associated macrophage (TAM) transformation from M2 to M1, and ultimately boost the antitumor immunity. Upon laser irradiation, the introduction of IR820 and LA significantly contributes to accelerating the release of ferrous ions from ferritin in IL@FA NPs to further induce the ferroptosis of the tumor cells. The ferroptosis-induced immunogenic cell death (ICD) of tumor cells could promote DC maturation and activate cytotoxic CD8⁺ T cells. Meanwhile, upon laser irradiation, reactive oxygen species (ROS), produced by IL@FA NPs, can facilitate DC maturation and M2-to-M1 repolarization of TAMs. Effective tumor growth suppression was realized by IL@FA NPs without showing toxicities. This study presents a promising "three birds with one stone" strategy to synergistically reinforce the ferroptosis of tumor cells, DC maturation, and TAM repolarization from M2 to M1 for enhanced cancer immunotherapy.