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<p>Tumor necrosis factor receptor 2-positive regulatory T (TNFR2<sup>+</sup> T<sub>reg</sub>) cells, the most suppressive subset of T<sub>reg</sub> cells, are enriched in malignant pleural effusion (MPE), contributing to disease progression. However, the underlying mechanisms responsible for their accumulation remain unclear. Here we demonstrate that the C–X–C motif chemokine ligand 16 (CXCL16)/C–X–C chemokine receptor type 6 (CXCR6) axis plays a critical role in recruiting TNFR2<sup>+</sup> T<sub>reg</sub> cells to MPE, with cancer-associated fibroblasts serving as the primary source of CXCL16. Mechanistically, under the hypoxic conditions prevailing in the pleural cavity, cancer-associated fibroblasts in MPE undergo glycolysis, which in turn leads to an increase in the production of endogenous lactate. This elevated lactate induces histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of both the CXCL16 gene and its transcription factor forkhead box O3 (FOXO3), which may contribute to CXCL16 transcription. TNFR2<sup>+</sup> T<sub>reg</sub> cells that express high levels of CXCR6, the only receptor for CXCL16, are subsequently recruited into MPE. The infiltration of TNFR2<sup>+</sup> T<sub>reg</sub> cells may reinforce the immunosuppressive milieu of MPE, facilitating disease progression. Collectively, these findings uncover a novel mechanism governing immunosuppression in MPE, providing new insights into potential therapeutic strategies to disrupt this process.</p>

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H3K18 lactylation in cancer-associated fibroblasts drives malignant pleural effusion progression via TNFR2+ Treg recruitment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Linlin Ye,
  • Xuan Xiang,
  • Zihao Wang,
  • Siyu Zhang,
  • Qianqian Xue,
  • Xiaoshan Wei,
  • Yao Liu,
  • Haolei Wang,
  • Jiaqi Ai,
  • Bohan Yang,
  • Long Chen,
  • Yiran Niu,
  • Wenbei Peng,
  • Qiong Zhou

摘要

Tumor necrosis factor receptor 2-positive regulatory T (TNFR2+ Treg) cells, the most suppressive subset of Treg cells, are enriched in malignant pleural effusion (MPE), contributing to disease progression. However, the underlying mechanisms responsible for their accumulation remain unclear. Here we demonstrate that the C–X–C motif chemokine ligand 16 (CXCL16)/C–X–C chemokine receptor type 6 (CXCR6) axis plays a critical role in recruiting TNFR2+ Treg cells to MPE, with cancer-associated fibroblasts serving as the primary source of CXCL16. Mechanistically, under the hypoxic conditions prevailing in the pleural cavity, cancer-associated fibroblasts in MPE undergo glycolysis, which in turn leads to an increase in the production of endogenous lactate. This elevated lactate induces histone H3 lysine 18 lactylation (H3K18la) at the promoter regions of both the CXCL16 gene and its transcription factor forkhead box O3 (FOXO3), which may contribute to CXCL16 transcription. TNFR2+ Treg cells that express high levels of CXCR6, the only receptor for CXCL16, are subsequently recruited into MPE. The infiltration of TNFR2+ Treg cells may reinforce the immunosuppressive milieu of MPE, facilitating disease progression. Collectively, these findings uncover a novel mechanism governing immunosuppression in MPE, providing new insights into potential therapeutic strategies to disrupt this process.