TGF-β Blockade With SB525334 Enhances B7-H3 CAR-γδT Cell Efficacy Against Glioblastoma.

Transforming growth factor-beta (TGF-β) signalling promotes glioblastoma (GBM) immunosuppression and therapy resistance. Although CAR-γδT therapy has shown promising efficacy in hematologic malignancies, its application to solid tumours-particularly GBM-is impeded by multiple factors, including a highly immunosuppressive tumour microenvironment, inefficient T-cell infiltration, T-cell exhaustion driven by inhibitory pathways such as TGF-β, and antigen heterogeneity. Bioinformatics analyses further corroborate that TGFB1 is significantly upregulated in GBM and correlates with poor prognosis, highlighting TGF-β as a pivotal mediator of therapeutic resistance. This study aimed to evaluate whether SB525334, a selective TGF-β receptor inhibitor, can enhance the efficacy and persistence of CAR-γδT cells in GBM. We demonstrate that SB525334 selectively enhances CAR-γδT cell function and antitumour efficacy by alleviating TGF-β-mediated immunosuppression and T-cell exhaustion while promoting immune activation within the GBM microenvironment. The combination treatment significantly reduced tumour cell viability (approximately 40%-50% residual viability) compared to CAR-γδT therapy alone (70%-85% residual viability), indicating a clear synergistic effect. Unlike broad-spectrum inhibitors, SB525334 sustains CAR-γδT proliferative capacity and effector function under chronic antigen stimulation, remodels the immunosuppressive tumour microenvironment, and promotes a pro-inflammatory immune signature. Our findings establish a combination strategy to overcome immunosuppressive barriers that limit current CAR-γδT therapies in solid tumours. By maintaining T-cell function and remodelling the tumour immune microenvironment, TGF-β1 small-molecule inhibitors show potential as translational adjuvants to broaden the clinical applicability of CAR-γδT cell immunotherapy.