Intrinsic tumor-targeted murine Ferritin nanocage co-delivers GPX4 and FSP1 inhibitors for synergistic ferroptosis-immunotherapy

Colorectal cancer patients, especially microsatellite stable patients, have no response to immunotherapy due to the immunosuppressive microenvironment. Ferroptosis has been reported to be immunogenic and can enhance the intratumoral infiltration of CD8+ T lymphocytes, which in turn enforce tumor ferroptosis through released interferon gamma. Herein, a murine Ferritin (mHFn) was constructed by genetic engineering and used to specifically co-deliver RSL3 and iFSP1 to tumor tissue, taking advantage of its high affinity with transferrin receptor (TfR) that were highly expressed on tumor cells. mHFn@RSL3/iFSP1 simultaneously inhibited GPX4 and FSP1 antioxidant pathways, significantly causing intracellular ROS accumulation, lipid peroxidation and final ferroptotic cell death. The immunogenic ferroptosis further stimulated the immune system and promoted the intratumoral infiltration of CD8+ T cells. Thanks to the mutual enhancement, the combination of mHFn@RSL3/iFSP1-based ferroptosis and alpha-PD-L1-based immunotherapy synergistically generated a strong long-term antitumor immune response to eradicate CT26 tumors, prevent tumor recurrence, and protect mice against live tumor cells challenge. The good biocompatibility, intrinsic tumor-targeting and systemically available immunostimulatory made mHFn@RSL3/iFSP1 a promising candidate for ferroptosis-immunotherapy against colorectal cancer.