Zhao, YunLiu, ZhongshunLiu, GuoqiangZhang, YutingLiu, ShengGan, DailinChang, WennanPeng, XiaoxiaSung, Eun SuhGilbert, KeeganZhu, YiniWang, XuechunZeng, ZiyuBaldwin, HopeRen, GuanzhuWeaver, JessicaHuron, AnnaMayberry, ToniWang, QingfeiWang, YujueDiaz-Rubio, Maria ElenaSu, XiaoyangStack, M. SharonZhang, SiyuanLu, XueminSheldon, Ryan D.Li, JunZhang, ChiWan, JunLu, Xin2024-11-112024-11-112023Zhao Y, Liu Z, Liu G, et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 2023;35(10):1688-1703.e10. doi:10.1016/j.cmet.2023.09.004https://hdl.handle.net/1805/44476Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.en-USPublisher PolicyAcod1MDSCBreast cancerFerroptosisImmune checkpoint blockadeImmune metabolismItaconateMetastasisNeutrophilSingle-cell RNA sequencingArticle