Mukherjee Siddhartha, Garda Cindy, Boffa Letizia, Elia Angela Rita, Massara Matteo, Balia Maria Teresa, Brina Daniela, Mosole Simone, Campagnari Anna, Cassanmagnago Giada Andrea, Rinaldi Andrea, Lazzaroni Giacomo, Jarrossay David, Morone Diego, Ceppi Ilaria, De Sillo Riccardo, Giacomini Isabella, Craparotta Ilaria, Di Rito Laura, Barry Simon, Laczko Endre, Streb Sebastian, Meani Francesco, Di Lascio Simona, Hynes Nancy, Lugli Enrico, Puccio Simone, Sammut Stephen-John, Perriard Ulrike, Harder Yves, Rossi Lorenzo, Gasparri Maria Luisa, Bolis Marco, Cejka Petr, Calcinotto Arianna
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Università della Svizzera italiana, Faculty of Biomedical Sciences, Lugano, Switzerland.
Nat Commun. 2025 Jul 30;16(1):6999. doi: 10.1038/s41467-025-61422-9.
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.
肿瘤进化是产生治疗抗性和更具侵袭性的癌症克隆的主要机制之一。肿瘤微环境是否通过免疫介导机制促进更具侵袭性的癌症类型的发展，对于确定更多治疗机会至关重要。在此，我们鉴定出了肿瘤相关中性粒细胞的一个亚群，定义为肿瘤相关中性粒细胞前体（PreNeu）。这些PreNeu在高度增殖的激素依赖性乳腺癌中富集，并损害DNA修复能力。从机制上讲，肿瘤相关PreNeu分泌的琥珀酸抑制同源重组，通过由PARP-1调节的非同源末端连接促进易出错的DNA修复。因此，乳腺癌细胞获得基因组不稳定性，促进肿瘤编辑和进展。对这些途径的选择性抑制在体外和体内均诱导增加的肿瘤细胞杀伤。肿瘤相关PreNeu评分与乳腺癌患者高度增殖的激素依赖性肿瘤中的拷贝数改变相关。用PARP-1抑制剂治疗可抵消这些中性粒细胞的促肿瘤作用，并与内分泌治疗协同作用。
