Biomineralized bacterial outer membrane vesicles exert pleiotropic immunoferroptotic effects on immune-deserted liver cancer

Abstract The immune landscape of late-stage liver cancer is featured by severe immunosuppression that is characterized by poor immunogenicity, T-cell exhaustion, and infiltration of a large number of immunosuppressive cells, leading to compromised therapeutic efficacy of mainstream immunotherapies. Herein, we developed a pleiotropic immunoferroptotic mobilization strategy to treat intractable advanced liver cancer. In this study, immunogenic bacteria-derived outer membrane vesicles (OMVs) were exploited as a vector to deposit Cu and Mn with mixed valence states via one-step biomineralization, followed by platelet membrane camouflage to enhance the circulation time and reduce systemic side effects of the metal biomineralized OMVs, which are denoted as OPCM. Mechanistically, the metal-deposited OPCM possesses POD, CAT, and GPX-like activities, thereby stimulating immunogenic ferroptosis, cGAS-STING activation, and tumor hypoxia alleviation, ultimately leading to pleiotropic immunoferroptotic mobilization to combat tumor growth, recurrence, and metastasis. Notably, the combination with typical αPD-L1 augmented the tumor suppression effect, since the administration of αPD-L1 not only rescued exhausted T cells, but also amplified the intensity of ferroptosis due to IFN-γ secretion by activated T cells. Overall, the metal biomineralized OPCMs in combination with αPD-L1 formed a closed-loop therapy that cycles from immunotherapy and ferroptosis therapy, providing new insights for treating immunosuppressive liver cancer.