Xu Nannan, Zhu Yemin, Han Yichao, Liu Qi, Tong Lingfeng, Li Yakui, Chen Zhangbing, Shao Sijia, He Wenrui, Li Mingrui, Wang Yi, Qiang Siyuan, Chai Peiwei, Du Peng, Zhao Wenyi, Wu Lifang, Zhang Ping, He Jianli, Li Hecheng, Cheng Jinke, Jia Renbing, Li Bin, Lu Ying, Tong Xuemei
Department 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.
Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Metab. 2025 Aug 22. doi: 10.1038/s42255-025-01347-1.
In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (T) immunosuppressive function and restraining CD8 T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both T and CD8 T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient T cells, loss of MondoA enhanced CD8 T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8 T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.
在肿瘤微环境中，积累的乳酸（LA）通过促进调节性T细胞（Treg）的免疫抑制功能和抑制CD8+ T细胞的细胞毒性来促进肿瘤免疫逃逸，但其潜在机制仍不清楚。在此，我们报告转录因子MondoA诱导的硫氧还蛋白相互作用蛋白（TXNIP）转录是Treg和CD8+ T细胞对乳酸反应的共同特征。与MondoA缺陷型Treg细胞免疫抑制能力降低相反，在乳酸诱导的免疫抑制微环境中，MondoA的缺失通过恢复葡萄糖摄取和糖酵解增强了CD8+ T细胞的细胞毒性功能。机制上，乳酸依赖于类泛素特异性蛋白酶1（SENP1）来刺激MondoA-TXNIP轴，这损害了TCR/CD28信号诱导的CD8+ T细胞活化。重要的是，靶向MondoA-TXNIP轴可增强多种癌症类型的抗肿瘤免疫力，并与抗PD-1疗法协同作用，以促进结直肠癌中有效的T细胞反应。我们的结果表明，MondoA-TXNIP轴是改善癌症免疫治疗的一个有前景的治疗靶点。
