Qian Yi-Yu, Jin Ning, Rao Shan-Shan, Wang Ya, Li Xin, Pan Wen, Huang Pu, Wang Si-Yuan, Li Ping-Fei, Lv Yan-Kai, Gao Qing-Lei, Xia Yu
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.
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.
NPJ Breast Cancer. 2025 Jul 7;11(1):67. doi: 10.1038/s41523-025-00785-0.
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.
乳腺癌（BC）通常被称为“冷肿瘤”，因为其免疫抑制细胞密集，尤其是M2样巨噬细胞，这导致其对治疗产生抗性。因此，迫切需要将巨噬细胞极化转向M1，并恢复肿瘤免疫微环境（TIME）以改善BC的预后。在本研究中，我们利用已发表的RNA测序数据，并对临床标本进行多重免疫组化，以确定NR4A3是BC预后良好的一个有前景的生物标志物。高NR4A3表达与炎症性TIME相关，其特征是T细胞浸润和激活增加。NR4A3在巨噬细胞中优先表达，并通过直接结合p65促进M1样巨噬细胞极化，从而增强NF-κB转录活性。在同基因小鼠模型中，肿瘤浸润巨噬细胞中Nr4a3的过表达显著抑制了E0771肿瘤的生长，同时T细胞浸润增加，功能性细胞因子的产生也增加。相反，巨噬细胞中Nr4a3的抑制损害了T细胞募集并降低了它们的抗肿瘤能力。与这些发现一致，涉及人T细胞和过表达NR4A3的THP1细胞的共培养实验进一步证明了T细胞功能增强。总的来说，我们的发现揭示了NR4A3在巨噬细胞极化和TIME重塑中的新作用，为BC预后良好提供了一个潜在的生物标志物，并为提高免疫治疗疗效提供了一个治疗靶点。
