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<p>T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. Here we used an epigenetic drug screen and identified bromodomain and extra-terminal motif inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells (T<sub>EX</sub>) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate T<sub>EX</sub> cells by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (<i>ODC1</i>), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated that BETis reduced terminal T<sub>EX</sub> while promoting progenitor T<sub>EX</sub> through activation of the MYC–ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic–metabolic approach to enhance T<sub>EX</sub> plasticity and offer insights for novel cancer immunotherapies.</p>

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Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer

  • 期刊论文

  • 发表日期：

    2026年5月12日

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  • Yi-Chieh Wu,
  • Shih-Feng Yang,
  • Yu-Ting Lee,
  • Meng-Wei Chou,
  • Shu-Yung Lin,
  • Yu-Ching Wang,
  • Sheng-Yao Su,
  • Chia-Lang Hsu,
  • Nai-Wen Chang,
  • Yi-Jhen Huang,
  • Yi-Hsiu Juan,
  • Hsuan-Hsuan Lu,
  • Chien-Yin Chen,
  • Yi-Fu Wang,
  • Po-Ju Lee,
  • Hsiao-Jung Kao,
  • Pei-Shan Wu,
  • Miao-Hsia Lin,
  • Li-Chung Hsu,
  • Yen-Ling Chiu,
  • Shih-Yu Chen,
  • Chong-Jen Yu,
  • Hsing-Chen Tsai

摘要

T cell exhaustion represents a critical target for immunotherapy in cancer. Nevertheless, T cells exhibit diminished responsiveness to immune checkpoint inhibitors once they transition to a terminally exhausted state. Here we used an epigenetic drug screen and identified bromodomain and extra-terminal motif inhibitors (BETis) as enhancers of effector functions in primary exhausted T cells (TEX) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate TEX cells by activating the polyamine biosynthesis pathway, expanding intracellular polyamine pools and altering chromatin accessibility. Genetic and pharmacological inhibition of ornithine decarboxylase (ODC1), a key enzyme in this pathway, abolished BETi-mediated immunopotentiation. Single-cell RNA-seq demonstrated that BETis reduced terminal TEX while promoting progenitor TEX through activation of the MYC–ODC axis. BETi treatment or adoptive transfer of BETi-treated T cells suppressed malignant pleural effusion formation in a syngeneic lung cancer model. These findings highlight an epigenetic–metabolic approach to enhance TEX plasticity and offer insights for novel cancer immunotherapies.