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

• DOI: 10.1158/0008-5472.can-24-2531
• Publication Date: 2025-03-11T18:08:01Z
• Authors: Flaminia Pedretti; Mohmed Abdalfttah; Benedetta Pellegrino; Francesca Mateo; Paula Martínez-Sanz; Andrea Herencia-R...; Andreu Òdena; Pau Clavell-Revelles; Giorgia Casali; Heura Domenech; Laia Monserrat; Dražen Papić; Alba Mas Malavila; Anna Pascual-Reguant; Herena Eixarch; Marta Guzman; Olga Rodriguez; Judit Grueso; Sara Simonetti; Roberta Fasani; Paolo Nuciforo; Carmen Espejo; Stefan Florian; Miguel Ángel Pujana; Lara Nonell; Joan Seoane; Viia Valge-Archer; Mark J. O'Connor; Juan C. Nieto; Holger Heyn; Judith Balmaña; Alba Llop-Guevara; Violeta Serra

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.