Entanglement of Methylation Changes and cGAS-STING Signaling in Non-Small-Cell Lung Cancer

Background: cGAS-STING signaling has been primarily discovered as an important DNA sensing machinery, bridging innate immunity and adaptive immunity. Beyond its antiviral response, recent evidence expanded its complicated role in cancer therapy. Methods: UALCAN, The TCGA Wander, GEPIA, SMART, TIMER, Kaplan-Meier plotter, TCGA Data, and cBioPortal were utilized in the investigation. Results: We evaluated the expression of four key molecules (MB21D1, TMEM173, TBK1, and IRF3) in the cGAS-STING pathway and found that the TMEM173 gene was significantly downregulated in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Not only immunostimulatory cells but also regulatory T cells were triggered by the DNA sensing pathway. With gene enrichment analysis, we revealed that cell cycle and mechanotransduction/cytoskeleton signals were most closely connected with cGAS-STING signal alterations in non-small-cell lung cancer (NSCLC). cGAS-STING signaling was robustly correlated with methylation changes, especially histone H3K4 lysine demethylase KDM5s. Transient activation of cGAS-STING was found to exert tumor surveillance effect, and inhibition of STING signaling co-opt elevated KDM5 demethylases might inadvertently worsen clinical outcomes. Conclusion: cGAS-STING signaling and KDM5 demethylases have the potential to be used as targets for evaluating an effective immune response in the tumor microenvironment.