Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1-deficient breast cancer by repressing IRF3

Poly(ADP-ribose) polymerase 1 (PARP1) inhibition represents a promising targeted therapy for BRCA-deficient cancer patients based on the synthetic lethality theory. 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-polycytidylic 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.