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Jaeckel, E.* ; Friedman, S.L.* ; Hudecek, M.* ; Protzer, U.

Chimeric antigen receptor (CAR) T-cell therapy: Engineering immune cells to treat liver diseases.

J. Hepatol. 83, 1156-1171 (2025)

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Endogenous T cells recognize antigens through human leukocyte antigen (HLA)/peptide complexes. However, the polymorphism of HLA has posed significant challenges to the development of broadly applicable adoptive T-cell therapies. Engineered T cells can circumvent this barrier by targeting surface antigens independently from HLA through a synthetic chimeric antigen receptor (CAR) with an antibody-derived recognition domain fused to intracellular signaling motifs. CAR-T cell therapies have transformed the treatment of B-cell malignancies in hematology, and recent studies demonstrate therapeutic potential against solid tumors. This review presents an overview of CAR technology's fundamental principles and achievements, focusing on CAR-T cell applications in hepatic viral infections, autoimmune liver disease, and hepatobiliary tumors. Emerging senolytic therapies that target senescent cells and hepatic fibrosis are highlighted alongside regulatory CAR-T cells that induce liver-specific immune tolerance in transplantation. Future and ongoing research is reviewed that seeks to enhance the specificity, efficacy, and safety of CAR-based therapies as "living drugs" that facilitate targeted, sustained, and personalized interventions for liver diseases.

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