IRG1/itaconate/NRF2/GSH axis in tumor-associated macrophages drives therapy resistance and immune evasion in BRCA1-deficient breast cancer
Year: 2025
Type: preprint
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.
Authors: Yabing Nan, Sophie O’keefe, Xiadi He, Qingyu Luo, Xiaowei Wu, Jing Ni, Yutian Zou, Jerryd Marcus Meade, Yutong Li, Renlei Ji, Anwaruddin Mohammad, Pankaj Kumar, Qiwei Wang, Jean J. Zhao
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G3261725791, HARNESSING HOST INNATE IMMUNITY WITH INNOVATIVE THERAPEUTIC STRATEGIES IN TRIPLE-NEGATIVE BREAST CANCER, G5884675678, Cancer Research Training Program: From Molecular Mechanisms to Therapeutic Strategies, Dana Farber/Harvard Cancer Center Specialized Program of Research Excellence in Breast Cancer, Targeting Replication Stress and DNA Damage Response in Uterine Cancer, Integrating targeted therapy and immunotherapy to break through cancer
OpenAlex ID: W4415203271