The article reviews the role of cGAS/STING signaling in glioblastoma and its therapeutic potential. STING signaling is crucial for priming antitumor immunity, but it is epigenetically silenced in glioma cells, likely due to promoter methylation. Preclinical studies suggest that inducing cGAS/STING signaling in the glioma microenvironment could enhance antitumor responses. The authors discuss the compartment-specific roles of STING signaling in the tumor microenvironment, including its effects on immune cells and stromal cells. They also explore various therapeutic approaches to target STING signaling, such as STING agonists, alternating electric field therapy (TTFs), radiation therapy, and oncolytic viruses. Despite initial setbacks, preclinical and early clinical trials of STING agonists have shown promise, particularly when combined with other therapies. The article highlights the need for further research to optimize the timing and dosage of STING activation and to understand the potential inflammatory and neurotoxic effects of these therapies. Overall, the review underscores the therapeutic potential of targeting cGAS/STING signaling in glioblastoma, despite the challenges posed by the immunosuppressive nature of the tumor microenvironment.The article reviews the role of cGAS/STING signaling in glioblastoma and its therapeutic potential. STING signaling is crucial for priming antitumor immunity, but it is epigenetically silenced in glioma cells, likely due to promoter methylation. Preclinical studies suggest that inducing cGAS/STING signaling in the glioma microenvironment could enhance antitumor responses. The authors discuss the compartment-specific roles of STING signaling in the tumor microenvironment, including its effects on immune cells and stromal cells. They also explore various therapeutic approaches to target STING signaling, such as STING agonists, alternating electric field therapy (TTFs), radiation therapy, and oncolytic viruses. Despite initial setbacks, preclinical and early clinical trials of STING agonists have shown promise, particularly when combined with other therapies. The article highlights the need for further research to optimize the timing and dosage of STING activation and to understand the potential inflammatory and neurotoxic effects of these therapies. Overall, the review underscores the therapeutic potential of targeting cGAS/STING signaling in glioblastoma, despite the challenges posed by the immunosuppressive nature of the tumor microenvironment.