Zhang Qun, Tian Qiusi, Deng Rongzhen, Liu Keli, Chen Shiqun, Hu Shaofan, Zhang Zhengwen, Lu Hongzhao, Zhang Yiguo
The Laboratory of Cell Biochemistry and Topogenetic Regulation, College of Bioengineering and Faculty of Medical Sciences, Chongqing University, Chongqing, China.
Department of Neurosurgery, 3201 Hospital of Xi'an Jiaotong University Health Science Center, Hanzhong, China.
CNS Neurosci Ther. 2025 Jul;31(7):e70488. doi: 10.1111/cns.70488.
A pivotal role of cancer (e.g., glioma) microenvironment is primarily executed by tumor-associated macrophages (TAMs) in facilitating cancer immune evasion and even resisting immunotherapies. However, the molecular base for governing such functionality of TAMs remains poorly understood. Thereby, we here explore the impact of such a key regulatory transcription factor NFE2L1 (also called Nrf1) on glioma-relevant TAMs.
A set of combining in vivo and in vitro experimental approaches, e.g., by utilizing CRISPR-Cas9 and overexpression plasmids to modulate NFE2L1 expression, and the resulting phenotypic changes in TAMs were evaluated. Besides, immunofluorescence, RT-qPCR and flow cytometry were conducted to assay the infiltration of various immune cells, such as CD8+ T cells and M1-type macrophages, in the glioma microenvironment, as well as their therapeutic response to anti-PD1 treatment.
Deficiency of NFE2L1 causes a unique phenotypic switch in the TAMs from its pro-cancer M2-type to another anti-cancer M1-type, thereby inhibiting malignant progression of glioma. Such NFE2L1-deficiency leads to significantly increases of CD8+ T cells and M1 macrophages within tumor tissues of glioma and hence enhances its sensitivity to anti-PD1 therapy. Further experimental evidence has provided revealing a synergistic efficacy triggered by combined therapy of CD38 inhibitor with PD1 antibodies, significantly inhibited tumor growth, compared to that of their monotherapy. The mechanistic study unraveled that NFE2L1 enables for directly binding to those ARE sites within the promoter regions of both CD38 and PD-L1 genes in order to govern their transcriptional expression.
The aberrant role of NFE2L1 in the malignant progression of glioma was discovered in this study. It is of crucial significance to emphasize the potential of NFE2L1 inhibition as a strategic approach to enhance the efficacy of immunotherapeutic intervention. Overall, this discovery holds a substantial promise for advancement of innovative combination therapies, potentially enhancing treatment outcomes for individuals afflicted with glioma.
癌症（如胶质瘤）微环境的关键作用主要由肿瘤相关巨噬细胞（TAM）执行，以促进癌症免疫逃逸甚至抵抗免疫治疗。然而，调控TAM这种功能的分子基础仍知之甚少。因此，我们在此探讨关键调控转录因子NFE2L1（也称为Nrf1）对胶质瘤相关TAM的影响。
采用一系列体内和体外实验方法，例如利用CRISPR-Cas9和过表达质粒调节NFE2L1表达，并评估TAM中由此产生的表型变化。此外，进行免疫荧光、RT-qPCR和流式细胞术，以检测胶质瘤微环境中各种免疫细胞（如CD8+T细胞和M1型巨噬细胞）的浸润情况，以及它们对抗PD1治疗的反应。
NFE2L1缺陷导致TAM从促癌M2型转变为另一种抗癌M1型的独特表型转换，从而抑制胶质瘤的恶性进展。这种NFE2L1缺陷导致胶质瘤肿瘤组织内CD8+T细胞和M1巨噬细胞显著增加，从而增强其对抗PD1治疗的敏感性。进一步的实验证据表明，CD38抑制剂与PD1抗体联合治疗引发协同效应，与单一疗法相比，显著抑制肿瘤生长。机制研究表明，NFE2L1能够直接结合CD38和PD-L1基因启动子区域内的那些ARE位点，以调控它们的转录表达。
本研究发现了NFE2L1在胶质瘤恶性进展中的异常作用。强调抑制NFE2L1作为增强免疫治疗干预疗效的战略方法的潜力至关重要。总体而言，这一发现为创新联合疗法的发展带来了巨大希望，有可能改善胶质瘤患者的治疗效果。
