2. Academic Validation
  3. Transcriptional dynamics of CD8+ T-cell exhaustion in immune checkpoint inhibitor resistance at single-cell resolution

Transcriptional dynamics of CD8+ T-cell exhaustion in immune checkpoint inhibitor resistance at single-cell resolution

  • Mol Cancer. 2025 Dec 11;24(1):306. doi: 10.1186/s12943-025-02468-7.
Tzu-Yang Tseng # 1 2,  Ching-Hung Hsieh # 3,  Hsuan-Cheng Huang 4,  Yu-Ching Wu 5,  Chiun Hsu 3 6,  Chia-Lang Hsu 7 8 9 10,  Da-Liang Ou 11 12,  Hsueh-Fen Juan 13 14 15 16
Affiliations

Affiliations

  • 1 Department of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 106, Taiwan.
  • 2 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., 106, Taipei, Taiwan.
  • 3 Graduate Institute of Oncology, National Taiwan University, No.2, Syujhou Rd., Taipei, 100, Taiwan.
  • 4 Institute of Biomedical Informatics, National Yang Ming Chao Tung University, No. 155, Sec. 2, Linong St., 112, Taipei, Taiwan.
  • 5 Department of Medical Research, National Taiwan University Hospital, No.7, Chung Shan S. Rd., Taipei, 100, Taiwan.
  • 6 Department of Medical Oncology, National Taiwan University Cancer Center, No. 57, Ln. 155, Sec. 3, Keelung Rd., 106, Taipei, Taiwan.
  • 7 Graduate Institute of Oncology, National Taiwan University, No.2, Syujhou Rd., Taipei, 100, Taiwan. chialanghsu@ntuh.gov.tw.
  • 8 Department of Medical Research, National Taiwan University Hospital, No.7, Chung Shan S. Rd., Taipei, 100, Taiwan. chialanghsu@ntuh.gov.tw.
  • 9 Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, No. 1, Sec. 1, Ren'ai Rd., 100, Taipei, Taiwan. chialanghsu@ntuh.gov.tw.
  • 10 Center for Computational and Systems Biology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., 106, Taipei, Taiwan. chialanghsu@ntuh.gov.tw.
  • 11 Graduate Institute of Oncology, National Taiwan University, No.2, Syujhou Rd., Taipei, 100, Taiwan. dlou@ntu.edu.tw.
  • 12 YongLin Institute of Health, National Taiwan University, No. 49, Fanglan Rd., 106, Taipei, Taiwan. dlou@ntu.edu.tw.
  • 13 Department of Life Science, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 106, Taiwan. yukijuan@ntu.edu.tw.
  • 14 Center for Computational and Systems Biology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., 106, Taipei, Taiwan. yukijuan@ntu.edu.tw.
  • 15 Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., 106, Taipei, Taiwan. yukijuan@ntu.edu.tw.
  • 16 Center for Advanced Computing and Imaging in Biomedicine, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., 106, Taipei, Taiwan. yukijuan@ntu.edu.tw.
  • # Contributed equally.
PMID: 41382107 DOI: 10.1186/s12943-025-02468-7
Abstract

Background: Tumor-specific CD8+ T lymphocytes play a critical role in Anticancer immunity but frequently become dysfunctional and exhausted within the immunosuppressive tumor microenvironment. Although immune checkpoint inhibitors can restore T-cell activity, resistance to these treatments remains a significant challenge. Therefore, understanding the transcriptional and regulatory mechanisms underlying CD8+ T-cell exhaustion is crucial for the development of effective therapies.

Methods: We developed two murine models of acquired immune checkpoint inhibitor resistance through prolonged anti-PD1 treatment. To gain insight into CD8+ T-cell exhaustion, we performed single-cell multiomics analysis, including both scRNA-seq and scATAC-seq, to capture gene expression profiles and chromatin accessibility. Moreover, we collected three external datasets to validate the results in silico. We further assessed the therapeutic potential of RUNX2 through marker expression and cytotoxicity assays.

Results: Our single-cell analysis revealed distinct T-cell subsets, including early and terminally exhausted populations, along with their exhaustion trajectories. RUNX2 was identified as a key transcription factor associated with CD8+ T-cell exhaustion in both models and correlated with immunotherapy response in clinical data. Additionally, functional marker expression and cytotoxicity assays demonstrated that inhibiting RUNX2 improved CD8+ T-cell cytotoxicity.

Conclusions: These findings highlight the role of RUNX2 as a crucial regulator of CD8+ T-cell exhaustion in the context of prolonged immune checkpoint inhibitor treatment. Targeting RUNX2 may provide a novel strategy to overcome immune checkpoint inhibitor resistance and enhance therapeutic efficacy, offering promising avenues for combination therapies.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12943-025-02468-7.

Keywords

Gene expression profiling – GEP; Hepatocellular carcinoma; Immune checkpoint inhibitor; Next generation sequencing – NGS; T cell.

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