Pre-activation of T cell immunity potentiates ferroptotic cell death through arachidonic acid hybridized nanovesicles

Abstract Ferroptotic tumor therapy is of highly significance to treat malignancies. Nevertheless, immune cells within the tumor immune microenvironment (TIME) are particularly susceptible to ferroptosis upon exposure to ferroptotic inducers, leading to the immunosuppression of TIME. In the present work, we report a dual activation strategy to initially pre-activate the T cells within TIME using genetically engineered cytolysin A-expressing outer membrane vesicles (OMVs) to enhance the interferon-γ (IFN-γ) production. We then deliver the homologous tumor cell membrane-hybridized liposomal nanovesicles containing arachidonic acid (MLipoAA) to the tumor cells for IFN-γ-potentiated ferroptosis. The combination treatment of OMVs and MLipoAA results in significant tumor destruction in colon CT26 tumor xenografts. This approach is also effective in combating tumor recurrence and metastasis. Mechanistically, the produced IFN-γ synergizes with arachidonic acid to trigger Acsl4-mediated tumor ferroptosis. The present work provides prominent immunopotentiations followed by selective tumor ferroptotic strategy with high effectiveness and biocompatibility, presenting a robust therapeutic strategy to conquer the immunosuppression drawback during in vivo ferroptotic therapy. Graphical Abstract Pre-Activation of T cell Immunity Potentiates Tumor Ferroptotic Cell Death