A Review of Recent Advances in Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and poses a major global health burden. It remains a leading cause of cancer-related death worldwide, with persistently high incidence and mortality in regions affected by chronic viral hepatitis, cirrhosis, alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease. Although surgical resection, liver transplantation, locoregional therapies, molecular targeted agents, and immune checkpoint inhibitors have improved treatment options, outcomes for advanced HCC remain unsatisfactory. Chimeric antigen receptor (CAR) T-cell therapy is an adoptive cellular immunotherapy in which T lymphocytes are genetically engineered to recognize tumor-associated antigens and eliminate malignant cells. CAR-T-cell therapy has achieved major clinical success in hematologic malignancies, but its application in HCC is still developing because of tumor heterogeneity, antigen escape, limited T-cell trafficking, and an immunosuppressive tumor microenvironment. Recent studies have investigated several HCC-associated targets, including glypican-3 (GPC3), carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), CD133, epidermal growth factor receptor variant III (EGFRvIII), B7 homolog 3 (B7H3), mucin 1 (MUC1), natural killer group 2 member D ligand (NKG2DL), programmed death-ligand 1 (PD-L1)/c-Met, CD147, CD44, and epithelial cell adhesion molecule (EpCAM). This article provides a target-oriented synthesis of HCC-related CAR-T-cell therapy, summarizes registered clinical studies according to antigen target, CAR design, trial phase, administration route, and available outcomes, and discusses how CAR structural evolution may influence therapeutic development in HCC. This article aims to review recent advances in CAR-T-cell therapy for hepatocellular carcinoma.