Solid Tumor Derived Extracellular Vesicles In Car T Cell Treatment

This study aims to elucidate the molecular mechanisms by which solid tumors resist CAR T cell therapy and explore strategies to overcome sEV-mediated immunosuppression in CAR T cell treatment. sEVs were purified from melanoma, oral carcinoma, and pancreatic ductal adenocarcinoma cell lines. CAR T cells were generated from mouse and human T cells. CAR T cells were engineered to express Serpin B9, a granzyme B inhibitor, to mitigate fratricide. Mice bearing solid tumors were used to evaluate CAR T cell therapeutic effects, combined with or without anti-PD-1 antibody treatment. Tumor-derived sEVs suppressed CAR T cell proliferation, migration, and cytotoxic function via PD-L1. Blocking sEV secretion improved CAR T cell infiltration, antitumor activity, and activated endogenous antitumor immunity. Tumor-derived sEVs carried tumor antigens, which were horizontally transferred to CAR T cells, triggering antigen recognition-induced fratricide. Serpin B9-armored CAR T cells exhibited reduced fratricide and significantly enhanced antitumor activity. Combined with anti-PD-1 antibody, these engineered CAR T cells achieved better tumor clearance compared to their parental CAR T cells. Solid tumors exploit sEVs as a dual defense mechanism by delivering immunosuppressive molecules and antigens to resist CAR T cells. Engineering CAR T cells (e.g., Serpin B9 expression) or targeting tumor sEV secretion significantly improves therapeutic outcomes. This study identifies tumor-derived sEVs as a novel therapeutic target and highlights the clinical potential of combining CAR T therapy with sEV inhibitors for solid tumors.