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

ABSTRACT 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.