Harnessing STING Signaling and Natural Killer Cells overcomes PARP Inhibitor Resistance in Homologous Recombination Deficient Breast Cancer

Abstract Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). HRD also activates the cyclic GMP–AMP synthase (cGAS)-STimulator of INterferon Genes (STING)-Interferon (IFN) pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of thirty-five breast cancer (BC) patient-derived xenografts (PDX) and mouse-derived allografts (MDA). PARPi sensitivity correlated with HRD, increased genomic instability, and activation of the cGAS-STING-IFN signaling pathway. Single-cell analyses showed that IFN signaling and IFN-based immune interactions were suppressed in preclinical models with acquired resistance to PARPi, lacking concomitant clonal expansion of functional CD8+ T cells. However, the combination of PARPi and a novel STING agonist (STINGa) increased immune infiltration and resulted in superior antitumor activity in these tumors. Notably, the efficacy of PARPi monotherapy and the combination treatment with a STINGa was dependent on Natural Killer (NK) cells. In agreement, BC patients with BRCA1/BRCA2 mutations and good responses to PARPi showed higher abundancy of CD56+ NK cells in the tumor microenvironment and treatment-engaged CD56bright NK cells in the peripheral immune compartment, compared to those with poor responses. Therefore, these findings propose the combination of PARPi and STINGa as a potential novel strategy to enhance the therapeutic response in patients with acquired PARPi resistance and highlight a pivotal role of NK cells in the PARPi antitumor activity.