Abstract / Summary
Abstract Hepatocellular carcinoma (HCC) accounts for a substantial proportion of cancer mortality worldwide, and clinical outcomes remain poor for patients with advanced disease. T cell receptor-engineered T cells (TCR-T) represent an attractive immunotherapeutic modality because they can recognize peptide epitopes derived from intracellular tumor proteins and displayed on the cell surface by major histocompatibility complex molecules. This review critically summarizes recent progress in TCR-T therapy for HCC, with particular emphasis on innovations in TCR engineering. We survey the current landscape of targetable antigens in HCC and current approaches for identifying therapeutic TCR candidates, followed by a discussion of TCR-T and review their major safety and toxicity concerns. Importantly, we discuss the key challenges that limit the clinical efficacy, particularly the immunosuppressive tumor microenvironment, antigen heterogeneity, HLA restriction, and limited T cell persistence. We further highlight emerging strategies to enhance therapeutic efficacy and safety, including genetic engineering, metabolic and functional optimization, combinational approaches, and controllable safety mechanisms. Special considerations regarding TCR-T therapy for HCC recurrence after liver transplantation are also discussed. Finally, we outline future directions centered on refined target selection, artificial intelligence-assisted TCR discovery and design, scalable manufacturing, biomarker-driven patient selection, and rigorous safety evaluation. These insights provide a structured perspective on the current status of TCR-T therapy and the key steps required to facilitate its clinical translation in HCC.