2. Academic Validation
  3. IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer

IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer

  • bioRxiv. 2025 Oct 15:2025.10.14.682312. doi: 10.1101/2025.10.14.682312.
Yabing Nan 1 2,  Sophie O'keefe 3 4,  Xiadi He 5,  Qingyu Luo 6 7,  Xiaowei Wu 1 8,  Jing Ni 1 2,  Yutian Zou 1,  Jerryd Marcus Meade 3 4,  Yutong Li 1 2,  Renlei Ji 1 2,  Anwaruddin Mohammad 9,  Pankaj Kumar 9 10,  Qiwei Wang 3 4 11,  Jean J Zhao 1 2 12
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Microbiology, Immunology & Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 4 University of Virginia Comprehensive Cancer Center, Charlottesville, VA, USA.
  • 5 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Lifecycle Health Management Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 7 One Patient One Cure, Boston, MA, USA.
  • 8 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Bioinformatics Core, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 10 Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 11 Beirne B. Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • 12 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
PMID: 41279612 DOI: 10.1101/2025.10.14.682312
Abstract

Tumor-associated macrophages (TAMs) are major contributors to immunosuppression and therapeutic resistance, including resistance to PARP inhibitors (PARPi) in BRCA1-deficient breast Cancer. However, the mechanisms underlying TAM-mediated PARPi resistance remain unclear. Here, we demonstrate that TAM-derived glutathione (GSH) impairs the efficacy of PARPi by protecting tumor cells from DNA damage and Ferroptosis while suppressing STING-mediated immune activation. Mechanistically, STAT5-driven upregulation of the IRG1/itaconate axis in TAMs rewires Mitochondrial Metabolism and activates NRF2-dependent GSH biosynthesis. GSH is subsequently released into the tumor microenvironment, where it is taken up by tumor cells, protecting them from PARPi-induced cytotoxicity and dampening immune responses. Pharmacological inhibition of IRG1 reverses these effects, restoring PARPi sensitivity and enhancing anti-tumor immunity in BRCA1-deficient tumor models. Collectively, these findings uncover a TAM-specific immunometabolic program that limits PARPi efficacy and highlight the IRG1/NRF2/GSH axis as a promising therapeutic target to improve treatment outcomes in BRCA1-associated breast Cancer.

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