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DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs

Larry Ng1, Vincent Tano1, Priyankaa Pitcheshwar1,2

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.

Science Immunology
|June 12, 2026
PubMed

Insights

DEAD-box RNA helicase 6 (DDX6) normally represses RNA editing to protect against immune activation. In cancer, DDX6 suppresses immunity by stabilizing dsRNA; its depletion activates anti-tumor immunity.

Area of Science:

  • Molecular Biology
  • Immunology
  • Cancer Research

Background:

  • Cellular double-stranded RNA (dsRNA) can trigger immune responses, mimicking viral RNA.
  • Adenosine deaminases acting on RNA 1 (ADAR1)-mediated RNA editing is thought to destabilize dsRNA, preventing self-attack.

Purpose of the Study:

  • To investigate the role of DEAD-box RNA helicase 6 (DDX6) in regulating RNA editing and immune activation.
  • To explore the dual function of DDX6 in normal physiology versus cancer.

Main Methods:

  • Investigated the interaction between DDX6 and ADAR1.
  • Analyzed DDX6's effect on adenosine-to-inosine (A-to-I) RNA editing in cytoplasmic dsRNA.
  • Assessed the impact of DDX6 depletion on dsRNA accumulation and immune signaling in tumor cells.

Main Results:

  • DDX6 acts as an RNA editing repressor, binding to dsRNA and preventing A-to-I editing at A:C mismatches.
  • This repression by DDX6 stabilizes dsRNA structure, suppressing interferon signaling and immune responses.
  • Tumor cell-specific DDX6 depletion leads to dsRNA buildup, activating intrinsic and extrinsic immunity to inhibit tumor growth.

Conclusions:

  • DDX6 plays a context-dependent role, protecting against immune activation normally but suppressing immunity in cancer.
  • RNA editing can stabilize dsRNA via I-C pairing, a process inhibited by DDX6.
  • Targeting DDX6 offers a potential strategy for cancer immunotherapy by leveraging RNA-mediated innate immune activation.

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