Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer PMID: 42120791

ADC Targets in Oncology

2026-04-10

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

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].

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_EX) from malignant pleural effusions in patients with lung Cancer. Transcriptomics, metabolomics and ATAC-seq analyses revealed that BETis reinvigorate T_EX 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_EX while promoting progenitor T_EX 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_EX plasticity and offer insights for novel Cancer immunotherapies.