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 Helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLCs). 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 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 where genomic instability contribute to pathology.

中文翻译：

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靶向 DHX9 触发小细胞肺癌的肿瘤固有干扰素反应和复制应激

通过细胞质核酸传感途径激活癌细胞的先天免疫，这种现象被称为“病毒拟态”，已成为将免疫学“冷”肿瘤转化为“热”肿瘤的有效策略。通过基于 CRISPR 的 RNA 解旋酶筛选，我们发现 DExD/H-box 解旋酶 9 (DHX9) 是小细胞肺癌 (SCLC) 中双链 RNA (dsRNA) 的有效抑制因子。DHX9 的耗竭诱导细胞质 dsRNA 的积累并触发肿瘤固有的先天免疫。有趣的是，消除 DHX9 还会诱导 R 环的异常积累，从而导致 SCLC 中 DNA 损伤衍生的细胞质 DNA 和复制应激增加。在体内，DHX9缺失促进了肿瘤生长的减少，同时诱导了更具免疫原性的肿瘤微环境，增强了对免疫检查点阻断的反应。这些发现表明，DHX9 是肿瘤内在先天免疫和复制应激的重要抑制因子，代表了 SCLC 和其他基因组不稳定性导致病理学的“冷”肿瘤的有希望的靶标。