ZNF689 loss impairs homologous recombination sensitizing triple-negative breast cancer to combined PARP and PD-L1 inhibition

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by a poor prognosis due to the lack of effective targeted therapies. While poly (ADP-ribose) polymerase (PARP) inhibitors benefit BRCA1/2-mutated TNBC, their efficacy in BRCA wild-type tumors remains limited. In this study, we uncover a critical role of zinc-finger protein 689 (ZNF689) in regulating homologous recombination (HR) repair in TNBC. Our findings reveal that in response to DNA damage, ZNF689 is phosphorylated by ATM and promotes NBS1 ubiquitination via E3 ligase SKP2, leading to the stabilization of the MRN complex and subsequent ATM activation, thereby facilitating HR repair. ZNF689 loss markedly enhances sensitivity to PARP inhibitors in TNBC, particularly when combined with paclitaxel. Furthermore, PARP inhibition upregulates PD-L1 expression in ZNF689-deficient TNBC cells through activation of the STING pathway. Notably, ZNF689 loss enhances the therapeutic efficacy of PARP inhibition plus anti-PD-L1 immunotherapy. Together, these findings suggest ZNF689 as a crucial regulator of HR repair and provide proof-of-concept for combining PARP inhibition and PD-L1 blockade in patients with ZNF689-low TNBC. While PARP inhibition is effective in patients with BRCA1/2-mutated triple-negative breast cancer (TNBC), its effect in BRCA wild-type TNBC is limited. Here, the authors identify a role of ZNF689 in regulation of homologous recombination repair via stabilization of the MRN complex, with ZNF689 deficiency conferring sensitivity to PARP inhibition, which upregulates PD-L1 expression and sensitizes tumors to combination therapy with anti-PD-L1 in TNBC.