Epigenetic STING silencing is developmentally conserved in gliomas and can be rescued by methyltransferase inhibition

STING cg16983159 methylation: a key factor for glioblastoma immunosuppression

“…It is odd for GBM to be immunosuppressive and have a “cold” TME, since GBM frequently carries cytoplasmic and extrachromosomal DNA, which normally should trigger the cGAS–STING signaling pathway. 1 By demonstrating the epigenetic silencing of STING in GBM cells and the immune reactivation by DNMTi decitabine, this study by Low et al certainly inspires for new combinatorial therapeutic strategies. Several issues must be solved though before DNMTis can be actually used in clinical treatment.…”

“…In a recent study published in Cancer Cell , Low et al shed a light on a novel DNA methylation pattern in the promoter region of the stimulator of interferon genes (STING), which may be a key factor for the “cold” tumor micro-environment (TME) of glioblastoma (GBM), contributing to its immunosuppression. 1 They have demonstrated that STING expression is epigenetically silenced by cg16983159 methylation in glioma cells as well as normal brain cells and this silencing can be rescued by DNA methyltransferase (DNMT) inhibition (Fig. 1 ).…”

“…1 ). 1

Fig. 1 Schematic diagram demonstrating the epigenetic mechanism regulating glioblastoma tumor micro-environment.

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“… 2 However, by using single-cell RNA-sequencing profiles and Illumina methylation arrays, Low et al found that although myeloid, endothelial and stromal cells still expressed STING in GBM patients, epigenetic silencing of STING expression in GBM cells alone had led to a “cold” TME, which made GBM suppressive to immunotherapy. 1 …”

“…1). 1 Cancer cells, especially those treated with radiation or chemotherapy, often contain high levels of cytosolic DNA. 2 The cGAS-STING signaling axis is the major sensor of cytosolic DNA and triggers the innate immune response.…”