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

• DOI: 10.1158/2159-8290.c.7100101
• Publication Date: 2024-03-01T12:02:16Z
• Authors: 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 Balacha...; Israel Cañadas
• Keywords: Replication

<div>Abstract<p>Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as “viral mimicry,” has emerged an effective strategy to convert immunologically “cold” tumors into “hot.” Through curated CRISPR-based screen of RNA helicases, we identified DExD/H-box helicase 9 (DHX9) potent repressor double-stranded (dsRNA) small cell lung cancers (SCLC). Depletion DHX9 induced accumulation dsRNA and triggered tumor-intrinsic immunity. Intriguingly, ablating also aberrant R-loops, which resulted increase DNA damage–derived replication stress SCLCs. <i>In vivo</i>, deletion promoted decrease tumor growth while inducing more immunogenic microenvironment, invigorating responsiveness immune-checkpoint blockade. These findings suggest that is crucial stress, representing promising target for SCLC other genomic instability contributes pathology.</p>Significance:<p>One trigger immune response within enhance immunotherapy efficacy by endogenous “virus-mimetic” accumulation. Here, identify viral-mimicry-inducing factor involved the suppression RNAs R-loops propose novel antitumor immunity.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-1523" target="_blank">See related commentary Chiappinelli, p. 389.</a></i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-14-3-ITI" target="_blank">This article featured Selected Articles from This Issue, 384</a></i></p></div>