Our findings highlight how a prominent feature of the tumor microenvironment, hypoxia, can perturb this essential cGAS-STING axis in immune cells, through hypoxic GBM-derived EVs repressing cGAS expression in macrophages, thereby inhibiting cGAS-STING pathway activation and type I IFN production, with direct consequences for anti-tumor immunity mediated by T cells. Here, STING1 is linked to glioblastoma.