Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

  • Cell Rep Med. 2025 Nov 18;6(11):102448. doi: 10.1016/j.xcrm.2025.102448.
Po-Hsien Chiu  1 ,  Kuan-Chen Lai  2 ,  Hung-Ling Wang  3 ,  Yao-Wen Chang  4 ,  Wen-Chi Wu  5 ,  Tien-Hua Chen  5 ,  Yu-Shuen Tsai  6 ,  Jie-Hong Song  6 ,  Nai-Yun Sun  6 ,  Gar-Yang Chau  7 ,  Wen-Liang Fang  7 ,  Ju-Pei Chen  6 ,  Hung-Ming Wang  8 ,  Huai-Cheng Huang  9 ,  Meng-Che Hsieh  10 ,  Chun-Hung Hua  11 ,  Ming-Yu Lien  12 ,  Yi-Fang Chang  13 ,  Hui-Ching Wang  14 ,  Chih-Yen Chien  15 ,  Tai-Lin Huang  16 ,  Chen-Chi Wang  17 ,  Yi-Chun Liu  18 ,  Jo-Pai Chen  19 ,  Wei-Chen Lu  19 ,  Ching-Yi Yiu  20 ,  Chien-Liang Lin  21 ,  Pei-Jen Lou  22 ,  Pen-Yuan Chu  23 ,  Shao-Chun Wang  24 ,  Mien-Chie Hung  25 ,  Muh-Hwa Yang  26
Affiliations
  • 1. Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan.
  • 2. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 3. Center for Molecular Medicine, China Medical University Hospital, Taichung 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 40402, Taiwan.
  • 4. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 5. Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
  • 6. Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 7. Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
  • 8. Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Taoyuan 333423, Taiwan.
  • 9. Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei 100225, Taiwan.
  • 10. Department of Hematology and Oncology, E-Da Cancer Hospital, Kaohsiung 824005, Taiwan.
  • 11. Department of Otorhinolaryngology, China Medical University Hospital, Taichung 404327, Taiwan.
  • 12. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan.
  • 13. Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei 104217, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, MacKay Memorial Hospital, Taitung 950408, Taiwan.
  • 14. Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807377, Taiwan.
  • 15. Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital, Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-sen University, Kaohsiung 833401, Taiwan.
  • 16. Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833401, Taiwan.
  • 17. Department of Otolaryngology-Head and Neck Surgery, Taichung Veterans General Hospital, Taichung 407219, Taiwan.
  • 18. Department of Radiation Oncology, Taichung Veterans General Hospital, Taichung 407219, Taiwan.
  • 19. Department of Oncology, National Taiwan University Hospital Yunlin Branch, Yunlin 632007, Taiwan.
  • 20. Department of Otolaryngology, Yumin Medical Corporation Yumin Hospital, Caotun, Nantou 542007, Taiwan.
  • 21. Division of Hematology-Oncology, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan 736402, Taiwan.
  • 22. Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100225, Taiwan.
  • 23. Department of Otolaryngology, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
  • 24. Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan; Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung 40402, Taiwan; Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, China Medical University, Taichung 40402, Taiwan.
  • 25. Center for Molecular Medicine, China Medical University Hospital, Taichung 406040, Taiwan; Research Center for Cancer Biology, China Medical University, Taichung 40402, Taiwan; Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, China Medical University, Taichung 40402, Taiwan.
  • 26. Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Department of Research and Education, Taipei City Hospital, Taipei 103212, Taiwan. Electronic address: [email protected].
PMID: 41205596 DOI: 10.1016/j.xcrm.2025.102448
Abstract

Sequential Cancer therapy presents a critical challenge, as the impact of prior treatments on immunotherapy remains unclear. Here, we demonstrate that therapeutic stress from prolonged cetuximab exposure induces tumor-intrinsic resistance to immune checkpoint blockade (ICB) in head and neck squamous cell carcinoma (HNSCC). In a multicenter analysis, extended cetuximab treatment correlates with poor ICB response and survival. Mechanistically, chronic therapeutic stress provokes an initial inflammatory response that transitions into immune resistance. A previously unknown post-translational modification, STAT1 lysine 637 acetylation, serves as the molecular switch driving this process. Triggered by treatment-induced tumor necrosis factor alpha (TNF-α), this acetylation impairs STAT1 dimerization and transcriptional activity, while treatment-induced interferon (IFN)-β promotes STAT1 phosphorylation at tyrosine 701 and subsequent degradation. These modifications disrupt tumor IFN-γ responsiveness. Importantly, STAT1 acetylation in pre-treatment tumor samples predicts ICB efficacy, underscoring its potential as a clinically relevant biomarker for guiding immunotherapy decisions.

Keywords
STAT1; acetylation; immune checkpoint blockade; inteferon gamma signaling.
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