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<p>In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (T<sub>reg</sub>) immunosuppressive function and restraining CD8<sup>+</sup> 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<sub>reg</sub> and CD8<sup>+</sup> T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in <i>MondoA</i>-deficient T<sub>reg</sub> cells, loss of MondoA enhanced CD8<sup>+</sup> 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<sup>+</sup> 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.</p>

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Targeting MondoA–TXNIP restores antitumour immunity in lactic-acid-induced immunosuppressive microenvironment

  • 期刊论文

  • 发表日期：

    2025年8月22日

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  • Nannan Xu,
  • Yemin Zhu,
  • Yichao Han,
  • Qi Liu,
  • Lingfeng Tong,
  • Yakui Li,
  • Zhangbing Chen,
  • Sijia Shao,
  • Wenrui He,
  • Mingrui Li,
  • Yi Wang,
  • Siyuan Qiang,
  • Peiwei Chai,
  • Peng Du,
  • Wenyi Zhao,
  • Lifang Wu,
  • Ping Zhang,
  • Jianli He,
  • Hecheng Li,
  • Jinke Cheng,
  • Renbing Jia,
  • Bin Li,
  • Ying Lu,
  • Xuemei Tong

摘要

In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) 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 Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg 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.