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Higher Education Press

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PARP inhibitors (PARPi) leverage synthetic lethality in BRCA-deficient cancers, yet intrinsic resistance limits therapeutic benefit. Through functional proteomics, this study uncovers that PARPi disrupts spliceosome function via enhancing PARP1-SF3B1 interaction, inducing alternative spliced mRNA and dsRNA accumulation that activates antiviral mimicry innate immunity. BRCA1 loss suppresses IRF3, attenuating this immune response and conferring resistance. Remarkably, poly(I:C), a dsRNA analog, sensitizes PARPi to enhance antitumor efficacy in vivo. The study reveals a novel role of BRCA1 in innate immunity and proposes a strategy to overcome PARPi resistance.

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HIGHER EDUCATION PRESS

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