Kleberg Jeremy, Nataraj Akhila, Xiao Yufeng, Podder Bristy R, Jin Zeng, Tithi Tanzia Islam, Zheng Guangrong, Smalley Keiran S M, Moser Emily K, Safe Stephen, Maharjan Chandra K, Kolb Ryan, Zhang Weizhou
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Department of Biochemistry and Molecular Biology, College of Liberal Arts and Sciences, University of Florida, Gainesville, FL 32610, USA.
Int J Mol Sci. 2025 May 30;26(11):5266. doi: 10.3390/ijms26115266.
Orphan nuclear receptor 4A1 (NR4A1, Nur77) plays a crucial role in regulating immune cell metabolism and function within the tumor microenvironment (TME), thus influencing cancer progression and serving as a potential therapeutic target for cancer immunotherapy. A comprehensive review discussing the multifaceted roles of NR4A1 in immune cells and the exploitation of that knowledge for therapeutic development is lacking in the field. This review explores diverse functions of NR4A1 in tumor-associated immune cells, including T cells, monocytes, natural killer cells, B cells, dendritic cells, macrophages, and neutrophils. NR4A1 contributes to immune regulation by impacting cytokine production, cell differentiation, and immune cell exhaustion. We highlight how NR4A1 in immune cells within the TME may be either a positive (e.g., macrophages in colon cancer) or negative prognostic factor (e.g., T cells in melanoma), depending on the cancer and immune cell context. Additionally, this review also highlights potential therapeutic strategies targeting NR4A1, leading to its inhibition, activation, or degradation to restore immune cell function and enhance anti-tumor immunity. Such therapies could potentially improve patient outcomes by altering immune cell behaviors, blocking intrinsic tumor growth pathways, or via both mechanisms. However, the development of NR4A1-targeted therapies will be dependent on further research to better understand lineage-specific roles of NR4A1 and the underlying mechanisms across different cancer types and immune cells.
孤儿核受体4A1（NR4A1，Nur77）在调节肿瘤微环境（TME）中的免疫细胞代谢和功能方面发挥着关键作用，从而影响癌症进展，并成为癌症免疫治疗的潜在靶点。该领域缺乏一篇全面综述来讨论NR4A1在免疫细胞中的多方面作用以及如何利用这些知识进行治疗开发。本综述探讨了NR4A1在肿瘤相关免疫细胞中的多种功能，包括T细胞、单核细胞、自然杀伤细胞、B细胞、树突状细胞、巨噬细胞和中性粒细胞。NR4A1通过影响细胞因子产生、细胞分化和免疫细胞耗竭来促进免疫调节。我们强调，根据癌症类型和免疫细胞背景，TME中免疫细胞内的NR4A1可能是一个积极的（如结肠癌中的巨噬细胞）或消极的预后因素（如黑色素瘤中的T细胞）。此外，本综述还强调了针对NR4A1的潜在治疗策略，通过抑制、激活或降解NR4A1来恢复免疫细胞功能并增强抗肿瘤免疫力。此类疗法可能通过改变免疫细胞行为、阻断肿瘤内在生长途径或通过这两种机制来改善患者预后。然而，NR4A1靶向疗法的开发将依赖于进一步研究，以更好地理解NR4A1在不同癌症类型和免疫细胞中的谱系特异性作用及潜在机制。
