Chiu, Po-HsienPo-HsienChiuLai, Kuan-ChenKuan-ChenLaiWang, Hung-LingHung-LingWangChang, Yao-WenYao-WenChangWu, Wen-ChiWen-ChiWuChen, Tien-HuaTien-HuaChenTsai, Yu-ShuenYu-ShuenTsaiSong, Jie-HongJie-HongSongSun, Nai-YunNai-YunSunChau, Gar-YangGar-YangChauFang, Wen-LiangWen-LiangFangChen, Ju-PeiJu-PeiChenWang, Hung-MingHung-MingWangHsieh, Meng-CheMeng-CheHsiehHUAI-CHENG HUANGHua, Chun-HungChun-HungHuaLien, Ming-YuMing-YuLienChang, Yi-FangYi-FangChangWang, Hui-ChingHui-ChingWangChien, Chih-YenChih-YenChienHuang, Tai-LinTai-LinHuangWang, Chen-ChiChen-ChiWangLiu, Yi-ChunYi-ChunLiuLu, Wei-ChenWei-ChenLuJO-PAI CHENYiu, Ching-YiChing-YiYiuLin, Chien-LiangChien-LiangLinPEI-JEN LOUChu, Pen-YuanPen-YuanChuWang, Shao-ChunShao-ChunWangHung, Mien-ChieMien-ChieHungYang, Muh-HwaMuh-HwaYang2026-03-262026-03-262025-11-18https://scholars.lib.ntu.edu.tw/handle/123456789/736863Sequential 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.enSTAT1acetylationimmune checkpoint blockadeinteferon gamma signalingjournal article10.1016/j.xcrm.2025.10244841205596