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Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma
Justin T Low1, Michael C Brown1, Zachary J Reitman2
1Department of Neurosurgery.
Abstract:
Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.
Insights
The cGAS/STING pathway recognizes cancer DNA to boost anti-tumor immunity. In gliomas, targeting this pathway in the tumor microenvironment shows therapeutic promise for brain cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway detects endogenous DNA from dying cancer cells, triggering type I interferon and T cell responses.
- Gliomas exhibit a unique immune microenvironment with limited T cells but abundant myeloid cells, contributing to poor responses to immune checkpoint blockade.
- STING expression is notably absent in malignant glioma cells, likely due to promoter methylation, unlike most extracranial tumors.
Purpose of the Study:
- To review the role of cGAS/STING signaling in gliomas and its implications for glioma immunobiology.
- To explore the compartment-specific functions of STING signaling in immune surveillance within the glioma context.
- To discuss current and emerging strategies for targeting the STING pathway, directly or indirectly, for anti-glioma therapy.
Main Methods:
- Review of preclinical studies and existing literature on cGAS/STING pathway in cancer, with a focus on gliomas.
- Analysis of the glioma immune microenvironment and its interaction with the cGAS/STING pathway.
- Discussion of therapeutic modalities that engage or are influenced by cGAS/STING signaling in glioblastoma.
Main Results:
- Preclinical data suggest that activating cGAS/STING signaling within the glioma immune microenvironment could offer therapeutic benefits.
- cGAS/STING signaling mediates inflammatory and antitumor effects of established and developing glioblastoma therapies, including radiation, tumor-treating fields, and oncolytic virotherapy.
- Understanding STING's role is crucial for developing effective immunotherapies for brain tumors.
Conclusions:
- Despite STING deficiency in glioma cells, the cGAS/STING pathway remains a viable target for enhancing anti-glioma immunity.
- Targeting STING, directly or indirectly, holds potential for improving therapeutic outcomes in glioblastoma.
- Further research into STING pathway modulation is warranted for novel brain cancer treatments.
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