{"doi":"10.1016/j.celrep.2025.116384","title":"Spliceosome inhibition induces Z-RNA and ZBP1-driven cell death in small cell lung cancer","abstract":"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 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.","journal":"Cell Reports","year":2025,"id":514955,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1201350,"name":"Xueying Ma","orcid":"0009-0006-5161-1073","position":1,"is_corresponding":false},{"id":390836,"name":"Yunyun Zhou","orcid":"0000-0003-1689-8575","position":2,"is_corresponding":false},{"id":1003114,"name":"Xiaodan Liu","orcid":"0000-0003-1995-4456","position":3,"is_corresponding":false},{"id":225721,"name":"Ting Zhang","orcid":"0000-0002-8645-581X","position":4,"is_corresponding":false},{"id":477804,"name":"William Kim","orcid":"0000-0002-3021-7193","position":5,"is_corresponding":false},{"id":225739,"name":"Siddharth Balachandran","orcid":"0000-0003-2084-1803","position":6,"is_corresponding":false},{"id":320276,"name":"Israel Cañadas","orcid":"0000-0001-6474-711X","position":7,"is_corresponding":false},{"id":318263,"name":"Xinpei Jiang","orcid":"0000-0003-2358-7580","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-19T02:48:34.431522Z","pmid":"41046514","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}