2. Academic Validation
  3. NR4A3 potentials M1-like macrophage polarization to facilitate anti-tumor immune responses in breast cancer

NR4A3 potentials M1-like macrophage polarization to facilitate anti-tumor immune responses in breast cancer

  • NPJ Breast Cancer. 2025 Jul 7;11(1):67. doi: 10.1038/s41523-025-00785-0.
Yi-Yu Qian # 1 2,  Ning Jin # 1 2,  Shan-Shan Rao 3,  Ya Wang 1 2,  Xin Li 1 2,  Wen Pan 1 2,  Pu Huang 4,  Si-Yuan Wang 5,  Ping-Fei Li 6,  Yan-Kai Lv 7,  Qing-Lei Gao 8 9,  Yu Xia 10 11
Affiliations

Affiliations

  • 1 Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Pathology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China.
  • 4 Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, China.
  • 5 Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 6 Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
  • 7 Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 8 Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. qlgao@tjh.tjmu.edu.cn.
  • 9 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. qlgao@tjh.tjmu.edu.cn.
  • 10 Cancer Biology Research Center (Key Laboratory of the Ministry of Education, Hubei Provincial Key Laboratory of Tumor Invasion and Metastasis), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Xiayu_hb@tjh.tjmu.edu.cn.
  • 11 National Clinical Research Center for Obstetrics and Gynecology, Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Xiayu_hb@tjh.tjmu.edu.cn.
  • # Contributed equally.
PMID: 40624019 DOI: 10.1038/s41523-025-00785-0
Abstract

Breast Cancer (BC) is commonly labeled a "cold tumor" due to its dense population of immunosuppressive cells, particularly M2-like macrophages, which contribute to its resistance to therapy. Thus, there is a pressing need to shift the macrophage polarization towards M1 and revitalize the tumor immune microenvironment (TIME) to improve BC prognosis. In this study, we leveraged published RNA-sequencing data and performed multiplex immunohistochemistry on clinical specimens to identify NR4A3 as a promising biomarker for favorable outcomes in BC. High NR4A3 expression correlates with an inflamed TIME, characterized by heightened T-cell infiltration and activation. NR4A3 was preferentially expressed in macrophages and fostered M1-like macrophage polarization through direct binding to p65, thereby enhancing NF-κB transcriptional activity. Overexpression of Nr4a3 in tumor-infiltrating macrophages significantly inhibited the growth of E0771 tumors in a syngeneic mouse model, accompanied by increased T-cell infiltration and elevated production of functional cytokines. Conversely, suppression of Nr4a3 in macrophages compromised T-cell recruitment and diminished their anti-tumor capabilities. Consistent with these findings, co-culture experiments involving human T cells and NR4A3-overexpressing THP1 cells further demonstrated enhanced T-cell functionality. Collectively, our findings uncover a novel role for NR4A3 in macrophage polarization and TIME remodeling, offering a potential biomarker for favorable BC prognosis and a therapeutic target to enhance immunotherapy efficacy.

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