Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1 PMID: 37793345

ADC Targets in Oncology

2026-04-10

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.

Yun Zhao ¹ , Zhongshun Liu ¹ , Guoqiang Liu ² , Yuting Zhang ² , Sheng Liu ³ , Dailin Gan ⁴ , Wennan Chang ⁵ , Xiaoxia Peng ¹ , Eun Suh Sung ¹ , Keegan Gilbert ¹ , Yini Zhu ² , Xuechun Wang ¹ , Ziyu Zeng ¹ , Hope Baldwin ¹ , Guanzhu Ren ¹ , Jessica Weaver ¹ , Anna Huron ¹ , Toni Mayberry ⁶ , Qingfei Wang ⁷ , Yujue Wang ⁸ , Maria Elena Diaz-Rubio ⁸ , Xiaoyang Su ⁹ , M Sharon Stack ¹⁰ , Siyuan Zhang ¹¹ , Xuemin Lu ¹ , Ryan D Sheldon ¹² , Jun Li ⁴ , Chi Zhang ⁵ , Jun Wan ¹³ , Xin Lu ¹⁴

Affiliations

1. Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
2. Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA.
3. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
4. Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA.
5. Department of Medical and Molecular Genetics and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Electrical and Computer Engineering, Purdue University, Indianapolis, IN 46202, USA.
6. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
7. Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
8. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
9. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA; Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
10. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
11. Department of Pathology, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
12. Mass Spectrometry Core, Van Andel Institute, Grand Rapids, MI, USA.
13. Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN 46556, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; School of Informatics and Computing, Indiana University - Purdue University at Indianapolis, Indianapolis, IN 46202, USA.
14. Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA; Tumor Microenvironment and Metastasis Program, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, IN 46202, USA. Electronic address: [email protected].

Abstract

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.