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Published on: August 1, 2025

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

Yi-Chieh Wu1, Shih-Feng Yang1, Yu-Ting Lee1

  • 1Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei City, Taiwan.

Nature Immunology
|May 12, 2026
PubMed

Insights

Bromodomain inhibitors (BETis) can enhance anti-cancer T-cell responses by targeting T-cell exhaustion. This epigenetic approach revitalizes exhausted T cells, offering a new avenue for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Epigenetics

Background:

  • T-cell exhaustion limits the effectiveness of cancer immunotherapies, particularly immune checkpoint inhibitors.
  • Terminally exhausted T cells display reduced responsiveness, hindering anti-tumor immunity.

Purpose of the Study:

  • To identify therapeutic strategies to overcome T-cell exhaustion in cancer.
  • To investigate the potential of epigenetic drugs to restore effector functions in exhausted T cells.

Main Methods:

  • Conducted an epigenetic drug screen to identify enhancers of exhausted T-cell (TEX) function.
  • Utilized transcriptomics, metabolomics, and ATAC-seq to analyze BETi effects on TEX cells.
  • Employed single-cell RNA-seq to assess BETi impact on TEX cell states and the MYC-ODC axis.
  • Evaluated BETi efficacy in a syngeneic lung cancer mouse model.

Main Results:

  • Bromodomain and extra-terminal motif inhibitors (BETis) were identified as enhancers of primary exhausted T cells from lung cancer patients.
  • BETis reinvigorate TEX cells by activating polyamine biosynthesis, increasing polyamine pools, and altering chromatin accessibility.
  • Inhibition of ornithine decarboxylase (ODC1) blocked BETi-mediated immunopotentiation.
  • BETis reduced terminal TEX and promoted progenitor TEX via the MYC-ODC axis.
  • BETi treatment suppressed tumor progression in a lung cancer model.

Conclusions:

  • Epigenetic modulation via BETis represents a promising strategy to enhance T-cell plasticity and combat cancer.
  • Activating the polyamine biosynthesis pathway is crucial for BETi-induced T-cell rejuvenation.
  • These findings provide a foundation for developing novel epigenetic-metabolic immunotherapies for cancer treatment.

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