Abstract Glioma remains a highly aggressive malignancy with frequent recurrence and resistance to radiotherapy and chemotherapy. BTN3A2 is a multifunctional regulatory protein originally implicated in γδ T-cell–mediated immune responses, yet its tumor-intrinsic role and mechanistic relevance in glioma are poorly defined. Here, BTN3A2 expression and prognostic associations were assessed in TCGA and CGGA cohorts and further validated by immunohistochemistry on tissue microarrays. Functional studies using lentivirus-mediated BTN3A2 knockdown demonstrated that BTN3A2 promotes glioma cell proliferation, migration, and invasion, and its depletion increases TMZ sensitivity in vitro and in vivo. Mechanistically, integrated RNA-seq, CUT&Tag, and promoter luciferase assays identified BTN3A2 as a hypoxia-responsive gene directly transcriptionally activated by HIF-1α. BTN3A2 subsequently enhanced DNA damage repair capacity through activation of the AKT/SP1/RAD51 axis, thereby contributing to TMZ resistance. Collectively, these findings establish BTN3A2 as a hypoxia-driven, cell-intrinsic mediator of glioma progression and chemoresistance, highlighting its potential value as a prognostic biomarker and therapeutic vulnerability.
Xu et al. (Sat,) studied this question.