Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer.
Journal
Nature immunology
ISSN
1529-2916
Date Issued
2026-05-12
Author(s)
Wu, Yi-Chieh
Yang, Shih-Feng
Lee, Yu-Ting
Chou, Meng-Wei
Wang, Yu-Ching
Su, Sheng-Yao
Chang, Nai-Wen
Huang, Yi-Jhen
Juan, Yi-Hsiu
Lu, Hsuan-Hsuan
Chen, Chien-Yin
Wang, Yi-Fu
Lee, Po-Ju
Kao, Hsiao-Jung
Wu, Pei-Shan
Lin, Miao-Hsia
Hsu, Li-Chung
Chiu, Yen-Ling
Tsai, Hsing-Chen
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 (T) from malignant pleural effusions in patients with lung cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate T 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 T while promoting progenitor T 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 plasticity and offer insights for novel cancer immunotherapies.
Type
journal article