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

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.

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.

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.

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.