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Nonsense-mediated mRNA decay inhibits TRAF6-dependent anti-tumor immunity in colorectal cancer

Yanmei Wang1, Zhuo Wang1, Chaoqun Wang2

  • 1Department of Medical Oncology, Cancer Center of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.

Cell Reports. Medicine
|November 20, 2025
PubMed

Insights

Targeting nonsense-mediated mRNA decay (NMD) in colorectal cancer (CRC) activates anti-tumor immunity and enhances immunotherapy. Inhibiting NMD reshapes the tumor microenvironment (TME), offering a promising new treatment strategy for CRC patients.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Colorectal cancer (CRC) immunotherapy efficacy is limited by low immunogenicity.
  • Nonsense-mediated mRNA decay (NMD) regulates gene expression, but its role in CRC and immunotherapy is unclear.
  • NMD activation and SMG5 upregulation were observed in CRC tissues.

Purpose of the Study:

  • To investigate the role of NMD in CRC and its impact on the tumor microenvironment (TME).
  • To evaluate the therapeutic potential of NMD inhibition in CRC, particularly in combination with immunotherapy.

Main Methods:

  • Utilized small interfering RNA (siRNA) targeting SMG5 and an NMD inhibitor (NMDI14) to inhibit NMD in CRC models.
  • Analyzed changes in the TME, including immune cell populations and activation status (e.g., CD8+ T cells).
  • Investigated the molecular mechanisms involving TBK1 and TRAF6 activation downstream of NMD inhibition.

Main Results:

  • NMD inhibition remodeled the TME, altering innate immune cells and enhancing CD8+ T cell activation.
  • NMD inhibition led to TBK1 activation via TRAF6 upregulation, with NMD targeting TRAF6 through its 3'-UTR.
  • High SMG5 and low TRAF6 expression correlated with poor response to immunotherapy.
  • Inhibiting NMD improved the efficacy of immune checkpoint blockade (ICB) therapy in CRC.

Conclusions:

  • Targeting NMD is a viable strategy to reconstruct the TME and enhance anti-tumor immunity in CRC.
  • NMD inhibition shows translational potential for improving immunotherapy response in colorectal cancer.
  • Understanding NMD's role in regulating immune responses offers new therapeutic avenues for CRC treatment.
Keywords:
NMDTRAF6colorectal cancertumor microenvironment

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