2. Academic Validation
  3. Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer

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

  • Nat Immunol. 2026 Jun;27(6):1268-1281. doi: 10.1038/s41590-026-02515-5.
Yi-Chieh Wu 1,  Shih-Feng Yang 1,  Yu-Ting Lee 1,  Meng-Wei Chou 1,  Shu-Yung Lin 2 3,  Yu-Ching Wang 1 4,  Sheng-Yao Su 1,  Chia-Lang Hsu 5,  Nai-Wen Chang 5,  Yi-Jhen Huang 1,  Yi-Hsiu Juan 2,  Hsuan-Hsuan Lu 2,  Chien-Yin Chen 6,  Yi-Fu Wang 7,  Po-Ju Lee 4 7,  Hsiao-Jung Kao 7,  Pei-Shan Wu 8 9,  Miao-Hsia Lin 8,  Li-Chung Hsu 6 10,  Yen-Ling Chiu 2 3 11 12,  Shih-Yu Chen 4 7,  Chong-Jen Yu 2 13,  Hsing-Chen Tsai 14 15 16 17 18 19
Affiliations

Affiliations

  • 1 Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 2 Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.
  • 3 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 4 Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
  • 5 Department of Medical Research, National Taiwan University Hospital, Taipei City, Taiwan.
  • 6 Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 7 Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
  • 8 Department of Microbiology, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 9 Center for Frontier Medicine, National Taiwan University Hospital, Taipei City, Taiwan.
  • 10 Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 11 Far Eastern Memorial Hospital, New Taipei City, Taiwan.
  • 12 Graduate Institute of Medicine, Yuan Ze University, Taoyuan, Taiwan.
  • 13 Department of Internal Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan.
  • 14 Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei City, Taiwan. [email protected].
  • 15 Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan. [email protected].
  • 16 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei City, Taiwan. [email protected].
  • 17 Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan. [email protected].
  • 18 Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan. [email protected].
  • 19 Center for Frontier Medicine, National Taiwan University Hospital, Taipei City, Taiwan. [email protected].
PMID: 42120791 DOI: 10.1038/s41590-026-02515-5
Abstract

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.

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