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向 MondoA-TXNIP 在乳酸诱导的免疫抑制微环境中恢复抗瘤免疫力

Nannan Xu¹, Yemin Zhu¹, Yichao Han²

¹Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Nature metabolism

|August 22, 2025

概括

瘤中的乳酸会抑制免疫细胞. 针对MondoA-TXNIP轴增强抗瘤免疫力和T细胞反应,提供一种新的癌症免疫治疗策略.

科学领域:

免疫学
癌症生物学
分子生物学

背景情况:

在瘤微环境 (TME) 中的乳酸积累驱动免疫逃避.
通过未知的机制,LA 损害了 CD8+ T 细胞的细胞毒性,并增强了调节性 T 细胞 (Treg) 免疫抑制.

研究的目的:

阐明乳酸如何影响T细胞在TME中的功能.
确定增强癌症免疫疗法的新疗法目标.

主要方法:

研究了转录因子MondoA和铁素相互作用蛋白 (TXNIP) 在暴露于乳酸的T细胞中的作用.
使用基因改造的T细胞 (MondoA缺乏) 并在体外和体内评估它们的功能.
研究了针对MondoA- TXNIP轴对各种癌症模型中的抗瘤免疫和与抗PD-1疗法的影响.

主要成果:

在Treg和CD8+T细胞中诱导MondoA依赖的TXNIP转录.
通过恢复葡萄糖代谢,MondoA缺乏减少了Treg免疫抑制和增强了CD8+T细胞的细胞毒性.
乳酸利用SENP1激活MondoA-TXNIP轴,抑制T细胞受体/CD28信号传递和T细胞激活.
针对MondoA-TXNIP轴增强了跨癌症类型的抗瘤免疫力,并与结直肠癌中的抗PD-1疗法协同作用.

结论:

在TME中,MondoA-TXNIP轴是乳酸诱导免疫抑制的关键媒介.
抑制MondoA- TXNIP轴是一种有前途的策略,可以增强T细胞介导的抗瘤免疫力,并提高癌症免疫疗法的疗效.

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