Dasatinib boosts γδ T cell expansion and memory phenotypes with enhanced antitumor immunity

Γδ T cells offer unique advantages in cancer immunotherapy because of their MHC-independent recognition of tumor antigens and innate cytotoxic potential. However, conventional ex vivo expansion protocols using zoledronic acid (Zol) and IL-2 often lead to terminal differentiation and diminished effector function. In this study, we performed a flow cytometry-based screen of an FDA-approved compound library to identify agents that enhance γδ T cell expansion while preserving their functional phenotypes. Dasatinib, a clinically used tyrosine kinase inhibitor, has emerged as a promising therapeutic candidate. Dasatinib-treated Vδ2 T cells (γδ2 T-Da) exhibited increased expansion, elevated expression of memory-associated markers (CD62L and CD127), reduced apoptosis, and higher production of TNF-α and IFN-γ. Transcriptomic analysis revealed the upregulation of genes related to T cell survival and self-renewal, including MYC, TCF7, and MIR155HG. Functionally, γδ2 T-Da cells demonstrated superior cytotoxicity against glioblastoma (GBM) and triple-negative breast cancer (TNBC) cells in vitro with sustained activity after prolonged culture. In orthotopic tumor models, γδ2 T-Da cells enhanced tumor control, reduced TNBC metastasis, and prolonged survival of GBM-bearing mice. These results suggest that dasatinib improves γδ T cell yield and function, providing a practical and translatable strategy for optimizing γδ T cell-based adoptive therapy, particularly for solid tumors.Trial registration: Trial number: CMUH111-REC3-185.