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The study shows that pharmacological or genetic neutralization of SF3B1 activity causes endogenous left-handed double-stranded Z-RNAs to accumulate. These Z-RNAs activate the Z-form nucleic-acid sensor ZBP1, driving cell death in mouse embryonic fibroblasts and small cell lung cancer cells. In vivo, ZBP1-dependent death in cancer-associated fibroblasts enhances immunotherapy response and supports a tumor-microenvironment, on-demand therapeutic mechanism.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/spliceosome-inhibition-induces-z-rna-and-zbp1-driven-cell-death-in-small-cell-lung-cancer-article/376525/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/spliceosome-inhibition-induces-z-rna-and-zbp1-driven-cell-death-in-small-cell-lung-cancer-article/376525.png","ImageObject",300,407,{"name":92,"@type":93},"CatatanPagi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How does spliceosome inhibition trigger antitumor effects in this study?","Question",{"text":112,"@type":113},"Spliceosome inhibition increases endogenous Z-RNAs, which activate the Z-form nucleic-acid sensor ZBP1, leading to cell death and strengthening antitumor immune responses.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What RNA species and sensor are central to the mechanism?",{"text":117,"@type":113},"Left-handed double-stranded Z-RNAs accumulate after SF3B1 neutralization and activate ZBP1 to initiate ZBP1-driven cell death.",{"name":119,"@type":110,"acceptedAnswer":120},"Why is cancer-associated fibroblast death important here?",{"text":121,"@type":113},"ZBP1-dependent cell death in cancer-associated fibroblasts is described as essential for enhancing immunotherapy responses in mouse models of small cell lung cancer.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},376525,1790925574,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Cell Rep. Author manuscript; available in PMC 2026 February 16. |\n| --- | --- |\n\nPublished in final edited form as:  \nCell Rep. 2025 October 28; 44(10): 116384. doi:10.1016/j.celrep.2025.116384 .  \nSpliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer  \nXinpei Jiang 1,2,3,4 , Xueying Ma 1,2,3 , Yunyun Zhou5 , Xiaodan Liu6 , Ting Zhang6,7,8 , William Kim9,10,11 , Siddharth Balachandran3,5 , Israel Cañadas 1,2,3,12,*  \n1 Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA  \n2Cancer Epigenetics Institute, Fox Change Cancer Center, Philadelphia, PA, USA  \n3Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA  \n4Biomedical Science Graduate Program, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA  \n5Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA  \n6Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China  \n7 Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China  \n8Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China  \n9Moores Cancer Center, UC San Diego, La Jolla, CA, USA  \n10Center for Novel Therapeutics, UC San Diego, La Jolla, CA, USA  \n11 Department of Medicine, UC San Diego, La Jolla, CA, USA  \n12Lead contact  \nSUMMARY  \nSpliceosome inhibitors emerged as promising anticancer agents. Recent studies have demonstrated that spliceosome-targeted therapies (STTs) trigger antitumor immune responses by inducing the accumulation of right-handed double-stranded (ds)RNA (A-RNA), resulting in the activation of RIG-I-like receptors (RLRs) and type I interferon-driven antiviral responses. Here, we show that spliceosome inhibition by pharmacological or genetic neutralization of SF3B1 activity induces the accumulation of endogenous left-handed dsRNAs (Z-RNAs) derived from intron-retained  \nThis is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).  \n*Correspondence: [israel.canadas@fccc.edu](israel.canadas@fccc.edu).  \nAUTHOR CONTRIBUTIONS  \nConceptualization, X.J., S.B., and I.C.; methodology X.J., X.M., Y.Z., X.L., T.Z., W.K., S.B., and I.C.; investigation: X.J. and I.C.; data acquisition, X.J.; data analysis and interpretation, X.J., Y.Z., and I.C.; writing and review, X.J., S.B., and I.C.; project administration, I.C.; and funding acquisition, X.J. and I.C.  \nDECLARATION OF INTERESTS  \nThe authors declare no competing interests.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nJiang et al. Page 2  \nRNAs. These Z-RNAs activate the Z-form nucleic acid-sensor ZBP1, which triggers cell death in mouse embryonic fibroblasts and small cell lung cancer (SCLC) cells. Spliceosome inhibition induced potent ZBP1-dependent cell death in cancer-associated fibroblasts, which was essential for enhancing immunotherapy response in mouse models of SCLC. Collectively, these results demonstrate that spliceosome inhibitors can be used to generate Z-RNA and trigger on-demand ZBP1-dependent cell death in cells of the tumor microenvironment (TME) as a therapeutic  \nstrategy to enhance immunotherapy responses in resistant cancers.  \nGraphical Abstract  \nIn brief  \nRNA splicing is frequently mutated in cancer and contributes to its pathogenesis. Jiang et al.  \ndemonstrate that spliceosome perturbation induces Z-RNAs, triggering ZBP1-dependent cell death in SCLC cells and CAFs and enhancing immunotherapy responses. Jiang et al. propose STTs as a strategy for therapeutic activation of ZBP1-induced necroptosis in cancer.  \nINTRODUCTION  \nSpliceosome deregulation, often caused during oncogenesis by pertu","cbCaiph1pxVwMthL","https://ap.wps.com/l/cbCaiph1pxVwMthL","pdf",2432188,43,"English","# Summary\n# Introduction\n## Spliceosome deregulation in cancer\n## Virus-mimetic dsRNA sensing and innate immune activation","[{\"question\":\"How does spliceosome inhibition trigger antitumor effects in this study?\",\"answer\":\"Spliceosome inhibition increases endogenous Z-RNAs, which activate the Z-form nucleic-acid sensor ZBP1, leading to cell death and strengthening antitumor immune responses.\"},{\"question\":\"What RNA species and sensor are central to the mechanism?\",\"answer\":\"Left-handed double-stranded Z-RNAs accumulate after SF3B1 neutralization and activate ZBP1 to initiate ZBP1-driven cell death.\"},{\"question\":\"Why is cancer-associated fibroblast death important here?\",\"answer\":\"ZBP1-dependent cell death in cancer-associated fibroblasts is described as essential for enhancing immunotherapy responses in mouse models of small cell lung cancer.\"}]","Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer - Article | PDF",1790219728,108]