Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma

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 mic...

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Bibliographic Details
Published in:The Journal of clinical investigation 2024-01, Vol.134 (2)
Main Authors: Low, Justin T, Brown, Michael C, Reitman, Zachary J, Bernstock, Joshua D, Markert, James M, Friedman, Gregory K, Waitkus, Matthew S, Bowie, Michelle L, Ashley, David M
Format: Article
Language:English
Subjects:
B cells
Biological response modifiers
Cancer
Care and treatment
Cellular signal transduction
Development and progression
DNA
Gene expression
Genetic aspects
Glioblastoma - therapy
Glioblastoma multiforme
Glioma
Humans
Interferon
Methylation
Nucleotidyltransferases - genetics
Nucleotidyltransferases - metabolism
Oncology, Experimental
Review
Signal Transduction
T cells
Tumor Microenvironment
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Summary: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.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI163452