Glioblastoma is one of the most intractable tumors and presents a hypoxic and immunologically cold microenvironment. Lee and colleagues demonstrate that normalizing oxygen tension unleashes gamma delta T cell anti-glioblastoma function. The anatomic location and immunologic characteristics of brain tumors result in strong lymphocyte suppression. Consequently, conventional immunotherapies targeting CD8 T cells are ineffective against brain tumors. Tumor cells escape immunosurveillance by various mechanisms and tumor cell metabolism can affect the metabolic states and functions of tumor-infiltrating lymphocytes. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected gamma delta T cell-mediated antitumor immune responses but not those of conventional T cells. Specifically, tumor hypoxia activated the gamma delta T cell protein kinase A pathway at a transcriptional level, resulting in repression of the activatory receptor NKG2D. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of gamma delta T cells. These results reveal a hypoxia-mediated mechanism through which brain tumors and gamma delta T cells interact and emphasize the importance of gamma delta T cells for antitumor immunity against brain tumors.