SRP287834 PRJNA670005 GSE159542 Tumor hypoxia represses ?d T cell-mediated antitumor immunity against brain tumors 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. Oxygen tension is one important factor influencing immune responses. Here, we discovered that brain tumor cells had a particularly high demand for oxygen, which affected ?d T-cell-mediated antitumor immune responses but not those of conventional T-cells. Specifically, tumor hypoxia activated the ?d T-cell protein kinase A (PKA) pathway at a transcriptional level, resulting in repression of NKG2D expression. Alleviating tumor hypoxia reinvigorated NKG2D expression and the antitumor function of ?d T-cells. These results reveal a hypoxia-mediated mechanism by which brain tumors and ?d T-cells interact and emphasize the importance of ?d T-cells for antitumor immunity against brain tumors. Overall design: 10X genomics was used to measure single-cell RNA sequencing (scRNA-seq) to characterize brain tumor-infiltrated immune cells. C57BL/6 mice were intracranially injected with GL261 cells. After 20 days of injection, brain cells were isolated. CD45hi TILs were isolated by FACS Aria. GSE159542 pubmed 33574616 pubmed 35990740