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.
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The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We acknowledge the support of the Key Laboratory of Drug Addiction Medicine of the National Health Commission, Kunming Medical University, Kunming, Yunnan, China.
Author contributions
ZXX conceived and designed the study, contributed to data collection, performed experiments, and participated in manuscript writing and revision; S.R.P. conceived and designed the study and contributed to data collection; XBH, BHL, JXZ, and JW helped conduct the experiments; JTT, XLY, SJY, and XCL analyzed and interpreted the data; XC, FCS, and JP supervised the study. FCS and JP wrote the manuscript. All authors read and approved the final manuscript.
Funding
This work was subsidized by the National Natural Science Foundation of China (Grant No. 82160512), the First-Class Discipline Team of Kunming Medical University (2024XKTDYS06,2024XKTDYS10), the Yunnan Fundamental Research Projects (Grant NO. 202401AS070018), the NHC Key Laboratory of Drug Addiction Medicine (KN202417) and the Kunming University of Science and Technology Medical Joint Special Project (KUST-PE2022011Y).
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All methods were performed in accordance with the relevant guidelines and regulations. The human glioma tissue microarray used for immunohistochemistry was commercially purchased from Shanghai Outdo Biotechnology Co., Ltd. (Product No. HBraG159Su01). The use of the human tissue microarray was reviewed and approved by the Ethics Committee of Shanghai Outdo Biotech Company (Approval No. SHYJS-CP-1801020). All human specimens were de-identified before being provided to the authors, and informed consent was obtained from all participants by the tissue provider prior to sample collection. No identifiable personal information was available to the authors. All animal experiments were approved by the Institutional Animal Care and Use Committee of the Second Affiliated Hospital of Kunming Medical University (Approval No. kyfey2023084) and were performed in accordance with the institutional guidelines for the care and use of laboratory animals.
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Xu, Z., Pu, S., Wu, J. et al. Hypoxia-induced BTN3A2 promotes glioma progression and chemoresistance via AKT/SP1/RAD51-mediated DNA damage. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08729-7
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DOI: https://doi.org/10.1038/s41419-026-08729-7
