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

Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to PARP inhibitors (PARPi). HRD also activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-interferon pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of 35 breast cancer patient-derived xenografts and mouse-derived allografts. 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 a 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, patients with breast cancer 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 with those with poor responses. Therefore, these findings propose the combination of PARPis and a 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. Significance: PARP inhibitor sensitivity is associated with cGAS-STING-IFN signaling, which can be harnessed by combining PARP inhibitors with STING agonists to overcome acquired resistance and requires NK cells to mediate antitumor immunity. See related commentary by Gohari et al., p. 1747.

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Journal
Cancer Research
Published
2025-03-11
DOI
https://doi.org/10.1158/0008-5472.can-24-2531
Citations
11
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
11.50
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article

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

Benedetta Pellegrino, Miguel Ángel Pujana, Laia Monserrat, Herena Eixarch et al.
11 citations
Cancer Research
PARP inhibition in cancer therapy
11.50
article

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

Benedetta Pellegrino, Miguel Ángel Pujana, Laia Monserrat, Herena Eixarch, Judit Grueso, Juan C. Nieto, Flaminia Pedretti, Roberta Fasani, Olga Rodríguez, Paula Martínez-Sanz, Mark J. O’Connor, Lara Nonell, S. Simonetti, Andreu Òdena, Dražen Papić, Joan Seoane, Alba Llop‐Guevara, Francesca Mateo, Stefan Florian, Holger Heyn, Anna Pascual Reguant, Violeta Serra, Carmen Espejo, Paolo Nucíforo, Andrea Herencia-Ropero, Judith Balmañà, Viia Valge-Archer, Marta Guzmán, Alba Mas Malavila, Heura Domènech, Gianluca Casali, Mohmed Abdalfttah, Pau Clavell-Revelles
article en
11 citations

Abstract

Homologous recombination deficiency (HRD) contributes to genomic instability and leads to sensitivity to PARP inhibitors (PARPi). HRD also activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-interferon pathway, highlighting the need to understand the impact of cGAS-STING-IFN signaling on PARPi efficacy. In this study, we analyzed a cohort of 35 breast cancer patient-derived xenografts and mouse-derived allografts. 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 a 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, patients with breast cancer 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 with those with poor responses. Therefore, these findings propose the combination of PARPis and a 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. Significance: PARP inhibitor sensitivity is associated with cGAS-STING-IFN signaling, which can be harnessed by combining PARP inhibitors with STING agonists to overcome acquired resistance and requires NK cells to mediate antitumor immunity. See related commentary by Gohari et al., p. 1747.

Cancer ResearchVol. 85(10)
AstraZeneca (United Kingdom) (GB), Institució Catalana de Recerca i Estudis Avançats (ES), Hebron University (PS), Universitat Autònoma de Barcelona (ES), University of Parma (IT), Generalitat de Catalunya (ES), Humboldt-Universität zu Berlin (DE), Institut d'Investigació Biomédica de Bellvitge (ES), Vall d'Hebron Institut de Recerca (ES), Institut Català d'Oncologia (ES), AstraZeneca (Singapore) (SG), Vall d'Hebron Hospital Universitari (ES), Centre for Genomic Regulation (ES), Centro Nacional de Análisis Genómico (ES), Vall d'Hebron Institute of Oncology (ES), Universitat de Barcelona (ES), Charité - Universitätsmedizin Berlin (DE)
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Openalex Percentile: Top 1%
PARP inhibition in cancer therapy
11.50
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