METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Nat Commun. 2021 Sep 17;12(1):5522. doi: 10.1038/s41467-021-25803-0.


Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N6-methyladenosine (m6A) methylation) is unclear. Here we report decreased expression of the m6A "writer" METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m6A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m6A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Gene Deletion
  • Homeostasis
  • Interleukin-15 / metabolism
  • Killer Cells, Natural / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Methylation
  • Methyltransferases / deficiency
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA / metabolism*
  • Signal Transduction
  • Tumor Microenvironment


  • Interleukin-15
  • RNA
  • N-methyladenosine
  • Methyltransferases
  • Mettl3 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse
  • Adenosine