Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1

• Published in: Cell metabolism 2023-10, Vol.35 (10), p.1688-1703.e10
• Main Authors: Zhao, Yun, Liu, Zhongshun, Liu, Guoqiang, Zhang, Yuting, Liu, Sheng, Gan, Dailin, Chang, Wennan, Peng, Xiaoxia, Sung, Eun Suh, Gilbert, Keegan, Zhu, Yini, Wang, Xuechun, Zeng, Ziyu, Baldwin, Hope, Ren, Guanzhu, Weaver, Jessica, Huron, Anna, Mayberry, Toni, Wang, Qingfei, Wang, Yujue, Diaz-Rubio, Maria Elena, Su, Xiaoyang, Stack, M. Sharon, Zhang, Siyuan, Lu, Xuemin, Sheldon, Ryan D., Li, Jun, Zhang, Chi, Wan, Jun, Lu, Xin
• Format: Article
• Language: English
• Subjects: Acod1; Animals; breast cancer; Breast Neoplasms - metabolism; Carboxy-Lyases - metabolism; Female; Ferroptosis; Humans; immune checkpoint blockade; immune metabolism; itaconate; MDSC; Melanoma, Cutaneous Malignant; metastasis; Mice; neutrophil; Neutrophils; single-cell RNA sequencing
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2023.09.004

Metastasis 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. [Display omitted] •Acod1 is an upregulated enzyme in murine and human tumor-infiltrating neutrophils•Acod1 upregulation is driven by the GM-CSF-JAK/STAT5-C/EBPβ signal pathway•Itaconate defends against ferroptosis and upholds neutrophils in metastasis•Acod1 ablation boosts the anti-metastasis efficacy of immune checkpoint blockade Zhao et al. report the induction of Acod1 in tumor-infiltrating neutrophils (TINs) and its critical role in blunting ferroptosis and sustaining viability for TINs. Acod1 ablation abates TIN density, constrains breast cancer metastasis, bolsters antitumor T cell immunity, and boosts the the anti-metastasis efficacy of immune checkpoint blockade in mice.