Targeting hepatocellular carcinoma with MAGE-A3-specific TCR-engineered T cells: A therapeutic approach.

[BACKGROUND AND AIMS] Hepatocellular carcinoma (HCC) exhibits limited therapeutic efficacy in current treatment strategies due to high recurrence rates and late-stage diagnosis. This study focuses on the tumor-specific antigen Melanoma-associated antigen A3 (MAGE-A3) to develop a human leukocyte antigen A2-restricted T-cell receptor-engineered T-cell (TCR-T) therapy, systematically evaluating its anti-HCC efficacy and underlying mechanisms.

[METHODS] MAGE-A3-specific TCR-T cells were engineered by introducing MAGE-A3-specific TCR genes into autologous T cells. Antigen expression and HLA-restricted T-cell recognition were validated, and antigen-specific cytotoxicity against HCC cell lines was assessed in vitro. Antitumor efficacy and safety were evaluated in subcutaneous xenograft models.

[RESULTS] Through The Cancer Genome Atlas (TCGA) data analysis and clinical specimen validation, we identified specific MAGE-A3 overexpression in HCC tissues, showing significant correlations with reduced overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) in patients (P < 0.05). Engineered MAGE-A3 antigen-specific TCR-T cells demonstrated significant cytotoxicity and induced target cell apoptosis in in vitro co-culture models. Mechanistic investigations revealed that TCR-T cells regulated apoptotic pathways through dual mechanisms: downregulation of p-AKT phosphorylation levels and activation of cleaved Caspase-3. In subcutaneous xenograft models, TCR-T therapy effectively suppressed tumor progression without observed organ toxicity.

[CONCLUSION] This study provides the first evidence supporting MAGE-A3 as a viable target for TCR-T therapy in HCC, proposing a novel immunotherapeutic strategy for solid tumors.