Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Takahiko Murayama, Jun Nakayama, Xinpei Jiang, Kenichi Miyata, Alexander D Morris, Kathy Q Cai, Rahul M Prasad, Xueying Ma, Andrey Efimov, Neel Belani, Emily R Gerstein, Yinfei Tan, Yan Zhou, William Kim, Reo Maruyama, Kerry S Campbell, Lu Chen, Yibin Yang, Siddharth Balachandran, Israel Canadas

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry,” has emerged as an effective strategy to convert immunologically “cold” tumors into “hot.” Through a curated CRISPR-based screen of RNA heli-cases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLC). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage–derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted a decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune-checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other “cold” tumors in which genomic instability contributes to pathology.

Original languageEnglish
Pages (from-to)468-491
Number of pages24
JournalCancer Discovery
Volume14
Issue number3
Early online dateDec 8 2024
DOIs
StateE-pub ahead of print - Dec 8 2024

Keywords

  • DEAD-box RNA Helicases/genetics
  • Humans
  • Immunity, Innate
  • Interferons
  • Lung Neoplasms/genetics
  • Neoplasm Proteins
  • Nucleic Acids
  • RNA, Double-Stranded
  • Small Cell Lung Carcinoma/genetics
  • Tumor Microenvironment

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