Tumor-associated neutrophil precursors impair homologous DNA repair and promote sensitivity to PARP inhibition

Siddhartha Mukherjee, Cindy Garda, Letizia Boffa, Angela Rita Elia, Matteo Massara, Maria Teresa Balia, Daniela Brina, Simone Mosole, Anna Campagnari, Giada Andrea Cassanmagnago, Andrea Rinaldi, Giacomo Lazzaroni, David Jarrossay, Diego Morone, Ilaria Ceppi, Riccardo De Sillo, Isabella Giacomini, Ilaria Craparotta, Laura Di Rito, Simon Barry, Endre Laczko, Sebastian Streb, Francesco Meani, Simona Di Lascio, Nancy Hynes, Enrico Lugli, Simone Puccio, Stephen-John Sammut, Ulrike Perriard, Yves Harder, Lorenzo Rossi, Maria Luisa Gasparri, Marco Bolis, Petr Cejka and Arianna Calcinotto ()
Additional contact information
Siddhartha Mukherjee: Oncology Institute of Southern Switzerland
Cindy Garda: Oncology Institute of Southern Switzerland
Letizia Boffa: Oncology Institute of Southern Switzerland
Angela Rita Elia: Oncology Institute of Southern Switzerland
Matteo Massara: Oncology Institute of Southern Switzerland
Maria Teresa Balia: Oncology Institute of Southern Switzerland
Daniela Brina: Oncology Institute of Southern Switzerland
Simone Mosole: Oncology Institute of Southern Switzerland
Anna Campagnari: Oncology Institute of Southern Switzerland
Giada Andrea Cassanmagnago: Oncology Institute of Southern Switzerland
Andrea Rinaldi: Oncology Institute of Southern Switzerland
Giacomo Lazzaroni: Oncology Institute of Southern Switzerland
David Jarrossay: Institute for Research in Biomedicine (IRB)
Diego Morone: Institute for Research in Biomedicine (IRB)
Ilaria Ceppi: Institute for Research in Biomedicine (IRB)
Riccardo De Sillo: Oncology Institute of Southern Switzerland
Isabella Giacomini: Oncology Institute of Southern Switzerland
Ilaria Craparotta: Istituto di Ricerche Farmacologiche ‘Mario Negri’ IRCCS
Laura Di Rito: Oncology Institute of Southern Switzerland
Simon Barry: AstraZeneca
Endre Laczko: ETH Zurich
Sebastian Streb: ETH Zurich
Francesco Meani: Ente Ospedaliero Cantonale
Simona Di Lascio: Ente Ospedaliero Cantonale Senology Center of Italian Switzerland
Nancy Hynes: Friedrich Miescher Institute for Biomedical Research
Enrico Lugli: IRCCS Humanitas Research Hospital
Simone Puccio: IRCCS Humanitas Research Hospital
Stephen-John Sammut: The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust
Ulrike Perriard: Ente Ospedaliero Cantonale
Yves Harder: Faculty of Biomedical Sciences
Lorenzo Rossi: Ente Ospedaliero Cantonale Senology Center of Italian Switzerland
Maria Luisa Gasparri: Ente Ospedaliero Cantonale
Marco Bolis: Oncology Institute of Southern Switzerland
Petr Cejka: Institute for Research in Biomedicine (IRB)
Arianna Calcinotto: Oncology Institute of Southern Switzerland

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutic opportunities. Here, we identify a subset of tumor-associated neutrophils, defined as tumor-associated neutrophil precursors (PreNeu). These PreNeu are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity. Mechanistically, succinate secreted by tumor-associated PreNeu inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire genomic instability promoting tumor editing and progression. Selective inhibition of these pathways induces increased tumor cell killing in vitro and in vivo. Tumor-associated PreNeu score correlates with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumoral effect of these neutrophils and synergize with endocrine therapy.

Date: 2025
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DOI: 10.1038/s41467-025-61422-9

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