| First Author | Zhao Y | Year | 2023 |
| Journal | Cell Metab | Volume | 35 |
| Issue | 10 | Pages | 1688-1703.e10 |
| PubMed ID | 37793345 | Mgi Jnum | J:341512 |
| Mgi Id | MGI:7540265 | Doi | 10.1016/j.cmet.2023.09.004 |
| Citation | Zhao Y, et al. (2023) Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab 35(10):1688-1703.e10 |
| abstractText | 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/EBPbeta 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. |
