CAR-T cells targeting activated hepatic stellate cells ameliorate liver fibrosis in mouse models

Background & Aims The transition to liver fibrosis represents a crucial and irreversible transition in chronic liver diseases, with liver fibrosis being a key driver of the progression to life-threatening complications, including cirrhosis and hepatocellular carcinoma (HCC). However, effective pharmacological therapies for liver fibrosis are lacking. Our study investigated the role of chimeric antigen receptor (CAR)-T cells in targeting and eliminating activated hepatic stellate cells (HSCs) for the treatment of liver fibrosis. Methods We engineered CAR-T cells targeting fibroblast activation protein (FAP), a cell surface protein specifically overexpressed on activated HSCs, and evaluated their therapeutic effects on liver fibrosis across four different mouse models. Results FAP CAR-T therapy significantly alleviated liver fibrosis across multiple etiologies ( p <0.0001, n=10). Mechanistically, the treatment specifically eliminated activated HSCs ( p <0.0001, n=10) and markedly increased hepatic T cell infiltration ( p <0.001, n=10). The antifibrotic efficacy of FAP CAR-T cells exceeded that of a FAP inhibitor ( p <0.001, n=6). Furthermore, the therapy effectively prevented the progression of HCC ( p <0.01, n=20). Conclusion Overall, our study shows that cell therapy targeting activated HSCs can ameliorate liver fibrosis and HCC, providing a novel therapeutic approach for these conditions. Impact and implications The global disease burden of liver fibrosis remains significant. Our study provides a novel therapeutic approach, demonstrating that cell therapy targeting activated HSCs can improve liver fibrosis and HCC. These results provide an important theoretical foundation for clinicians and translational researchers. Although further studies are needed to evaluate safety and efficacy before clinical translation, this approach could ultimately offer a cell therapy option to halt disease progression in patients with advanced liver fibrosis.