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

Cell Metab. 2023 Oct 3;35(10):1688-1703.e10. 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.

Keywords: Acod1; MDSC; breast cancer; ferroptosis; immune checkpoint blockade; immune metabolism; itaconate; metastasis; neutrophil; single-cell RNA sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms* / metabolism
  • Carboxy-Lyases* / metabolism
  • Female
  • Ferroptosis*
  • Humans
  • Melanoma, Cutaneous Malignant
  • Mice
  • Neutrophils


  • aconitate decarboxylase
  • Carboxy-Lyases