Cell metabolism · 2023
Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.