The cGAS/STING pathway plays a critical role in antitumor immunity by detecting cytosolic DNA and triggering type I interferon (IFN) responses, which activate immune cells such as T cells and natural killer (NK) cells. In glioblastoma (GBM), the immune microenvironment is characterized by low T cell infiltration and high myeloid cell presence, which limits the effectiveness of immune checkpoint inhibitors. However, STING signaling is largely absent in GBM tumor cells due to epigenetic silencing, primarily through promoter methylation. Despite this, preclinical studies suggest that inducing STING signaling in the GBM microenvironment could enhance antitumor immunity. cGAS/STING signaling has been shown to mediate the effects of various therapies, including radiation, tumor-treating fields, and oncolytic virotherapy. STING activation can be achieved through agonists, which stimulate the pathway and enhance IFN responses. However, clinical trials of STING agonists have shown limited success, possibly due to poor binding affinity to human STING. Recent studies have explored combination therapies, such as STING agonists with anti-CD47 antibodies or nanoparticles targeting both CD47 and PD-L1, which have shown promise in preclinical models. Additionally, alternating electric field therapy (TTF) and radiation therapy have been investigated for their ability to enhance STING signaling and antitumor immunity. Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are being explored for their ability to induce STING signaling and promote antitumor immune responses. Decitabine, a DNA hypomethylating agent, has shown potential in reactivating STING expression in GBM cells. However, the optimal timing and combination of STING activation with other therapies remain to be determined. The epigenetic silencing of STING in GBM presents both a challenge and an opportunity for therapeutic intervention. While STING activation may enhance immune responses, its role in the CNS environment requires careful consideration due to the risk of neurotoxicity. Future research aims to determine the best strategies for activating STING in GBM, including the use of epigenetic modulators, combination therapies, and novel delivery methods. The development of STING-targeted therapies for GBM remains an active area of research with potential for improving treatment outcomes.The cGAS/STING pathway plays a critical role in antitumor immunity by detecting cytosolic DNA and triggering type I interferon (IFN) responses, which activate immune cells such as T cells and natural killer (NK) cells. In glioblastoma (GBM), the immune microenvironment is characterized by low T cell infiltration and high myeloid cell presence, which limits the effectiveness of immune checkpoint inhibitors. However, STING signaling is largely absent in GBM tumor cells due to epigenetic silencing, primarily through promoter methylation. Despite this, preclinical studies suggest that inducing STING signaling in the GBM microenvironment could enhance antitumor immunity. cGAS/STING signaling has been shown to mediate the effects of various therapies, including radiation, tumor-treating fields, and oncolytic virotherapy. STING activation can be achieved through agonists, which stimulate the pathway and enhance IFN responses. However, clinical trials of STING agonists have shown limited success, possibly due to poor binding affinity to human STING. Recent studies have explored combination therapies, such as STING agonists with anti-CD47 antibodies or nanoparticles targeting both CD47 and PD-L1, which have shown promise in preclinical models. Additionally, alternating electric field therapy (TTF) and radiation therapy have been investigated for their ability to enhance STING signaling and antitumor immunity. Oncolytic viruses, such as oncolytic herpes simplex virus (oHSV), are being explored for their ability to induce STING signaling and promote antitumor immune responses. Decitabine, a DNA hypomethylating agent, has shown potential in reactivating STING expression in GBM cells. However, the optimal timing and combination of STING activation with other therapies remain to be determined. The epigenetic silencing of STING in GBM presents both a challenge and an opportunity for therapeutic intervention. While STING activation may enhance immune responses, its role in the CNS environment requires careful consideration due to the risk of neurotoxicity. Future research aims to determine the best strategies for activating STING in GBM, including the use of epigenetic modulators, combination therapies, and novel delivery methods. The development of STING-targeted therapies for GBM remains an active area of research with potential for improving treatment outcomes.