Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer - Article

Sep 24, 2026

Spliceosome inhibitors are presented as promising anticancer agents that reshape innate immunity by altering RNA species. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages43

Reading Time1 h 48 min

AccessFree to download

Summary

Introduction

Spliceosome deregulation in cancer

Virus-mimetic dsRNA sensing and innate immune activation

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Cell Rep. Author manuscript; available in PMC 2026 February 16. | | --- | --- | Published in final edited form as: Cell Rep. 2025 October 28; 44(10): 116384. doi:10.1016/j.celrep.2025.116384 . Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer Xinpei 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,* 1 Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA 2Cancer Epigenetics Institute, Fox Change Cancer Center, Philadelphia, PA, USA 3Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA 4Biomedical Science Graduate Program, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA 5Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA 6Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China 7 Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China 8Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, China 9Moores Cancer Center, UC San Diego, La Jolla, CA, USA 10Center for Novel Therapeutics, UC San Diego, La Jolla, CA, USA 11 Department of Medicine, UC San Diego, La Jolla, CA, USA 12Lead contact SUMMARY Spliceosome 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 This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). *Correspondence: [israel.canadas@fccc.edu](israel.canadas@fccc.edu). AUTHOR CONTRIBUTIONS Conceptualization, 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. DECLARATION OF INTERESTS The authors declare no competing interests. Author Manuscript Author Manuscript Author Manuscript Author Manuscript Jiang et al. Page 2 RNAs. 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 strategy to enhance immunotherapy responses in resistant cancers. Graphical Abstract In brief RNA splicing is frequently mutated in cancer and contributes to its pathogenesis. Jiang et al. demonstrate 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. INTRODUCTION Spliceosome deregulation, often caused during oncogenesis by pertu

FAQs

How does spliceosome inhibition trigger antitumor effects in this study?

Spliceosome inhibition increases endogenous Z-RNAs, which activate the Z-form nucleic-acid sensor ZBP1, leading to cell death and strengthening antitumor immune responses.

What RNA species and sensor are central to the mechanism?

Left-handed double-stranded Z-RNAs accumulate after SF3B1 neutralization and activate ZBP1 to initiate ZBP1-driven cell death.

Why is cancer-associated fibroblast death important here?

ZBP1-dependent cell death in cancer-associated fibroblasts is described as essential for enhancing immunotherapy responses in mouse models of small cell lung cancer.

Sep 24, 2026

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