DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs
Cellular double-stranded RNA (dsRNA) can activate immune pathways similar to viral RNA. Adenosine deaminases acting on RNA 1 (ADAR1)-mediated adenosine-to-inosine (A-to-I) RNA editing has long been believed to destabilize endogenous dsRNA, thus preventing immune activation. We identified DEAD-box RNA helicase 6 (DDX6) as a potent editing repressor and an immune protector under normal conditions but as an immunosuppressor in cancer contexts. Through its interaction with ADAR1, DDX6 binds preferentially to cytoplasmic dsRNA, repressing editing of adenosines in A:C mismatches across the transcriptome, disrupting dsRNA structural stability, and suppressing interferon signaling and immune responses. Depleting DDX6 in tumor cells triggers dsRNA accumulation and activates both intrinsic and extrinsic immunity to hinder tumor growth. Our findings broaden our understanding of the paradigm that RNA editing not only destabilizes cellular dsRNAs but also can stabilize them through I-C pairing, a process preferentially suppressed by DDX6, to limit cytosolic dsRNA sensor recognition. Targeting DDX6 and harnessing RNA-associated tumor cell-intrinsic innate immune activation holds promise for cancer immunotherapy.
Authors
- Han C. Chong (ORCID: https://orcid.org/0000-0002-8137-2556)
- Yangyang Song (ORCID: https://orcid.org/0000-0003-1666-2706)
- Wei Liang Gan (ORCID: https://orcid.org/0000-0001-9278-0718)
- Bin Wu (ORCID: https://orcid.org/0000-0002-0883-8006)
- Danielle Chin (ORCID: https://orcid.org/0000-0001-9391-9339)
- Daryl Jin Tai Tay (ORCID: https://orcid.org/0000-0002-4082-9281)
- Vanessa Hui En Ng (ORCID: https://orcid.org/0000-0001-8668-1801)
- Priyankaa Pitcheshwar (ORCID: https://orcid.org/0000-0003-4623-4307)
- Sze Jing Tang (ORCID: https://orcid.org/0000-0002-4258-6367)
- Haoqing Shen (ORCID: https://orcid.org/0000-0003-1721-1536)
- Dahai Luo (ORCID: https://orcid.org/0000-0001-7637-7275)
- Vincent Tano (ORCID: https://orcid.org/0000-0002-3573-9601)
- Ömer An (ORCID: https://orcid.org/0000-0002-5762-6253)
- Leilei Chen (ORCID: https://orcid.org/0000-0002-1987-3878)
- Jian Han (ORCID: https://orcid.org/0000-0003-2260-9784)
- Jesslyn Zhou
- Jinghe Xie
- Xi Ren
- Bryan Y.L. Ng
- Larry Ng (ORCID: https://orcid.org/0009-0005-8808-2083)
Institutions
- National University of Singapore (SG)
- Nanyang Technological University (SG)
- National University Cancer Institute, Singapore (SG)
- Central Hospital of Putuo District (CN)
- Guangdong Academy of Medical Sciences (CN)
- Guangdong Provincial People's Hospital (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2026-06-12
- DOI
- https://doi.org/10.1126/sciimmunol.aea6909
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00