Ligand-Receptor-Based Novel TWEAK CAR-T Exhibits Potent Antitumor Activity Against Liver Cancer by Targeting FN14

Liver cancer is the most frequent fatal malignancy, and existing treatments have limited efficacy. Tumor necrosis factor receptor superfamily member 12A (FN14) is highly expressed in liver cancer cells and promotes tumor cell proliferation, migration, invasion, and angiogenesis, suggesting that FN14 is a suitable therapeutic target for liver cancer. As a targeted therapy, chimeric antigen receptor T (CAR-T) cells have demonstrated potential for treating solid cancers. We designed a CAR targeting FN14 based on the extracellular domain of tumor necrosis factor superfamily member 12 (TWEAK), the only natural ligand for FN14, and tested its cytotoxic effect on tumor cells in vitro and in vivo. The results show that multiple liver cancer cell lines exhibit high FN14 expression. TWEAK-CAR-T cells specifically and effectively kill these cells in vitro. TWEAK-CAR-T cells also significantly suppress the growth of SK-Hep1 xenografts with high T-cell infiltration in the tumor. Moreover, potent and broad cytotoxicity of TWEAK-CAR-T was observed against diverse tumor cell lines from multiple cancer types. Our findings indicated that TWEAK-CAR-T cell therapy may be an effective therapeutic strategy for liver cancer.