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Recent evidence shows that the efficacy of DNA damage drugs depends on two aspects: DNA repair signaling and immune response. Applying a functional proteomics approach, we find that the function of the spliceosome is perturbed by PARP inhibitors via enhancing interaction between PARP1 and SF3B1, a key factor of the spliceosome. We demonstrate that differential alternative spliced mRNA and accumulation of double-stranded RNA (dsRNA) are induced by perturbation of the spliceosome upon PARP inhibitor treatment, resulting in triggering dsRNA antiviral mimicry innate immune response. Moreover, we identify a novel function of BRCA1, through which BRCA1 regulates innate immune response, leading to compromising of the innate immune signaling by downregulation of IRF3 in BRCA1-deficient breast cancer cells, which reduces the sensitivity to PARP inhibitors and causes intrinsic resistance. Polyinosinic\u2013polycytidylic acid (poly(I:C)) is a dsRNA synthetic analog sensitizing PARP inhibitors through further triggering dsRNA signaling. Finally, we show that the combination of PARP inhibitors and poly(I:C) enhances anti-tumor efficiency in vivo. Overall, our study reveals that BRCA1 deficiency impedes tumor cell intrinsic innate immune response, inducing intrinsic resistance to PARP inhibitors that can be overcome when poly(I:C) is combined.<\/jats:p>","DOI":"10.1093\/procel\/pwaf104","type":"journal-article","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T12:27:22Z","timestamp":1767529642000},"page":"616-630","source":"Crossref","is-referenced-by-count":1,"title":["Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1-deficient breast cancer by repressing IRF3"],"prefix":"10.1093","volume":"17","author":[{"given":"Cuiting","family":"Zhang","sequence":"first","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Bo","family":"Zhou","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh Haipeng","family":"Lei","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene Ling","family":"Ang","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Pilot Laboratory, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Institute of Translational Medicine, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Miao","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Xu","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence Chuen Wai","family":"Poon","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Pilot Laboratory, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Institute of Translational Medicine, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8034-2833","authenticated-orcid":false,"given":"Edwin","family":"Cheung","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision Medicine Research and Training, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"MoE Frontiers Science Center for Precision Oncology, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Faculty of Health Sciences, University of Macao , Taipa 999078, Macao,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8033-3902","authenticated-orcid":false,"given":"Chu-Xia","family":"Deng","sequence":"additional","affiliation":[{"name":"Cancer Centre, University of Macao , Taipa 999078, Macao,","place":["China"]},{"name":"Centre for Precision 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