2. Academic Validation
  3. Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

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

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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