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

Pan Feng1,2, Xiaolan Chen1, Dong Guo2

  • 1The Cancer Center, Fujian Medical University Union Hospital, Fuzhou, China.

Cellular and Molecular Life Sciences : CMLS
|May 25, 2026
PubMed

Insights

Cyclic GMP-AMP (cGAMP) influences the epitranscriptome by altering m6A methylation, revealing a new "cGAMP-FTO-m6A" axis. This axis is crucial for innate immunity and tumor progression, offering novel immunotherapy targets.

Area of Science:

  • Immunology
  • Epigenetics
  • Molecular Biology

Background:

  • Cyclic GMP-AMP (cGAMP) is a key second messenger in the cGAS-STING innate immune pathway, vital for antiviral and antitumor responses.
  • The precise regulatory mechanisms of cGAMP governing the epitranscriptome, specifically m6A methylation, are not fully understood.

Purpose of the Study:

  • To investigate the role of cGAMP in regulating m6A methylation within the epitranscriptome.
  • To elucidate the mechanistic link between cGAMP signaling, FTO expression, and the interferon response.
  • To explore the therapeutic potential of targeting the cGAMP-FTO-m6A axis in cancer immunotherapy.

Main Methods:

  • m6A methylation sequencing was performed on L929 and B16F10 cells treated with cGAMP.
  • Expression levels of the RNA demethylase FTO were analyzed following cGAMP treatment.
  • The impact of FTO deficiency on cGAMP-induced interferon-stimulated gene (ISG) expression and IFN-β secretion was assessed.
  • Correlation between dynamic m6A regulation of ISGs (e.g., DDX58) and tumor patient prognosis was analyzed.
  • In vivo experiments evaluated the combined antitumor effects of FTO inhibition and cGAMP treatment.

Main Results:

  • cGAMP induced dynamic changes in m6A modification patterns in the studied cell lines.
  • cGAMP treatment led to a significant downregulation of FTO expression.
  • FTO deficiency impaired cGAMP-mediated ISG expression and IFN-β secretion, highlighting FTO's role in bridging cGAMP signaling and interferon response.
  • Dynamic m6A regulation of ISGs, including DDX58, showed a close association with tumor patient prognosis and immune cell infiltration.
  • Combined inhibition of FTO and cGAMP administration demonstrated synergistic antitumor effects in vivo, suppressing tumor growth and improving survival.

Conclusions:

  • The study uncovers the
  • cGAMP-FTO-m6A
  • axis as a central mechanism in innate immunity and tumor progression.
  • This axis represents a novel regulatory pathway linking cGAMP signaling to the epitranscriptome and interferon response.
  • Targeting the FTO-mediated m6A regulation within this axis holds promise for developing innovative immunotherapies against cancer.
Keywords:
N 6-methyladenosine (m⁶A)FTOImmunotherapiescGAMPcGAS‒STING pathway

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