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m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA

Yucheng Wang1, Alice A Daddi1, Amir Hosseini1

  • 1Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford, UK.

Nature Communications
|May 14, 2026
PubMed

Insights

Cancer cells hide from immune detection by suppressing immunostimulatory retroelements. METTL3 inhibition reactivates anti-tumor immunity, offering a new therapeutic strategy for colorectal cancer (CRC).

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cancer cells can evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts.
  • Endogenous REs escaping epigenetic silencing in cancer form double-stranded RNA (dsRNA), activating innate immune responses via viral mimicry.
  • RNA-level mechanisms can limit the anti-tumor immune response.

Purpose of the Study:

  • To investigate the role of METTL3 in regulating immune suppression in colorectal cancer (CRC).
  • To explore the potential of targeting METTL3 as an immunotherapy strategy for CRC.

Main Methods:

  • Investigated the function of m6A RNA methyltransferase METTL3 in colorectal cancer.
  • Analyzed the accumulation of dsRNAs derived from retroelements upon METTL3 inhibition.
  • Assessed the impact of METTL3 inhibition on immunostimulatory signaling and anti-tumor immunity.
  • Evaluated the sensitivity of CRCs to METTL3 inhibition and combination therapies.

Main Results:

  • METTL3 acts as a key regulator suppressing immunostimulatory retroelement transcripts in CRC.
  • Targeting METTL3 increases dsRNA accumulation, amplifying immune signaling and activating cell-intrinsic anti-tumor immunity.
  • CRC sensitivity to METTL3 inhibition varies; low RNA methylation tumors require combination therapy with DNMT inhibitors.

Conclusions:

  • METTL3 functions as an RNA-level immune checkpoint in colorectal cancer.
  • Combined METTL3 and DNMT inhibition represents a promising therapeutic strategy for enhancing anti-tumor immunity in CRC.

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