Genome‐wide CRISPR screen reveals an uncharacterized spliceosome regulator as new candidate immunotherapy target

Cancer immune evasion is orchestrated by tumor-intrinsic molecular constraints that remain incompletely defined. Here, we performed an in vivo genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screen to catalogue gene regulatory determinants of immune evasion in cancer cells. We identify <i>C9ORF50</i> as a novel splicing regulator whose inhibition profoundly sensitizes cancer to immune surveillance. Integrated multi-omics profiling reveals this intrinsically disordered protein exhibits liquid-liquid phase separation properties and forms nuclear condensates that colocalize with spliceosome components. Genetic ablation correlates with intron retention in multiple spliceosome components and cytoplasmic accumulation of double-stranded RNA, which is associated with type I interferon activation and enhances chemokine-mediated T cell recruitment. As a result, <i>C9ORF50</i> inhibition amplifies tumor cell immunogenicity, enhancing T cell infiltration in poorly infiltrated tumors. Clinically, elevated <i>C9ORF50</i> expression correlates with poor survival and diminished lymphoid infiltration across malignancies. Therapeutic targeting of <i>C9ORF50</i> using RNA interference enhances T cell infiltration and suppresses tumor growth. Our work identifies <i>C9ORF50</i> as a candidate therapeutic target that modulates RNA splicing and tumor immunity, suggesting splicing regulation as a potential strategy to enhance immunotherapy responses.

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Publication Details

Journal
iMeta
Published
2025-11-28
DOI
https://doi.org/10.1002/imt2.70096
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
0.00
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article

Genome‐wide CRISPR screen reveals an uncharacterized spliceosome regulator as new candidate immunotherapy target

Jian-zhong Shao, Zhixiang Yuan, Jingyu Kuang, Wenjun Mao et al.
iMeta
RNA Research and Splicing
article

Genome‐wide CRISPR screen reveals an uncharacterized spliceosome regulator as new candidate immunotherapy target

Jian-zhong Shao, Zhixiang Yuan, Jingyu Kuang, Wenjun Mao, Lvyun Zhu, Aifu Lin, Tao Hou, Jingyang Wang, Guangchuan Wang, Chenghu Song, Yingying Li, Tong Shao, Yanhua Qi, Shaowei Zhang, Chuanyang Liu, Yu Liu, Jiali Liu, Lulu Zhang, Lingyun Zhu, Fangzhou Liu, Ying Qu, Sujuan Zhang, Sisi Xie, Yamei Hu, Ming Xing Li
article en

Abstract

Cancer immune evasion is orchestrated by tumor-intrinsic molecular constraints that remain incompletely defined. Here, we performed an in vivo genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) loss-of-function screen to catalogue gene regulatory determinants of immune evasion in cancer cells. We identify <i>C9ORF50</i> as a novel splicing regulator whose inhibition profoundly sensitizes cancer to immune surveillance. Integrated multi-omics profiling reveals this intrinsically disordered protein exhibits liquid-liquid phase separation properties and forms nuclear condensates that colocalize with spliceosome components. Genetic ablation correlates with intron retention in multiple spliceosome components and cytoplasmic accumulation of double-stranded RNA, which is associated with type I interferon activation and enhances chemokine-mediated T cell recruitment. As a result, <i>C9ORF50</i> inhibition amplifies tumor cell immunogenicity, enhancing T cell infiltration in poorly infiltrated tumors. Clinically, elevated <i>C9ORF50</i> expression correlates with poor survival and diminished lymphoid infiltration across malignancies. Therapeutic targeting of <i>C9ORF50</i> using RNA interference enhances T cell infiltration and suppresses tumor growth. Our work identifies <i>C9ORF50</i> as a candidate therapeutic target that modulates RNA splicing and tumor immunity, suggesting splicing regulation as a potential strategy to enhance immunotherapy responses.

iMetaVol. 4(6)
Central South University (CN), National University of Defense Technology (CN), Center for Excellence in Molecular Cell Science (CN), Second Xiangya Hospital of Central South University (CN), Wuxi People's Hospital (CN), China Academy of Launch Vehicle Technology (CN), Zhejiang University (CN)
Openalex Percentile: Top 66%
RNA Research and Splicing
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