Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

Po-Hsien Chiu¹, Kuan-Chen Lai², Hung-Ling Wang³, Yao-Wen Chang⁴, Wen-Chi Wu⁵, Tien-Hua Chen⁵, Yu-Shuen Tsai⁶, Jie-Hong Song⁶, Nai-Yun Sun⁶, Gar-Yang Chau⁷, Wen-Liang Fang⁷, Ju-Pei Chen⁶, Hung-Ming Wang⁸, Huai-Cheng Huang⁹, Meng-Che Hsieh¹⁰, Chun-Hung Hua¹¹, Ming-Yu Lien¹², Yi-Fang Chang¹³, Hui-Ching Wang¹⁴, Chih-Yen Chien¹⁵, Tai-Lin Huang¹⁶, Chen-Chi Wang¹⁷, Yi-Chun Liu¹⁸, Jo-Pai Chen¹⁹, Wei-Chen Lu¹⁹, Ching-Yi Yiu²⁰, Chien-Liang Lin²¹, Pei-Jen Lou²², Pen-Yuan Chu²³, Shao-Chun Wang²⁴, Mien-Chie Hung²⁵, Muh-Hwa Yang²⁶

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: mhyang2@nycu.edu.tw.

PMID: 41205596
DOI: 10.1016/j.xcrm.2025.102448

Free article

Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

Po-Hsien Chiu et al. Cell Rep Med. 2025.

Free article

. 2025 Nov 18;6(11):102448.

doi: 10.1016/j.xcrm.2025.102448. Epub 2025 Nov 7.

Authors

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: mhyang2@nycu.edu.tw.

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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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

Affiliations

Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous