cGAMP suppresses FTO expression to promote m6A modification and potentiate antitumor immunity

A modification in L929 and B16F10 cells. Mechanistic investigations revealed that cGAMP treatment significantly downregulated the expression of the RNA demethylase FTO. Although FTO deficiency suppresses cGAMP-induced interferon-stimulated gene (ISG) expression and IFN-β secretion, FTO may act as a critical node bridging cGAMP signaling and the interferon response. Further analysis revealed that the dynamic m⁶A regulation of ISGs, such as DDX58, is closely associated with the prognosis of tumor patients and immune cell infiltration. In vivo experiments confirmed that the targeted inhibition of FTO in combination with cGAMP exerts a synergistic antitumor effect, significantly suppressing tumor growth and prolonging survival. Overall, this study reveals the core mechanism of the "cGAMP-FTO-m⁶A" axis in innate immunity and tumor progression. These findings provide a theoretical foundation for the development of novel immunotherapies targeting the epitranscriptome.