Therapeutic stress triggers tumor STAT1 acetylation to disarm immunotherapy.
Journal
Cell Reports Medicine
Start Page
Article number 102448
ISSN
2666-3791
Date Issued
2025-11-18
Author(s)
Chiu, Po-Hsien
Lai, Kuan-Chen
Wang, Hung-Ling
Chang, Yao-Wen
Wu, Wen-Chi
Chen, Tien-Hua
Tsai, Yu-Shuen
Song, Jie-Hong
Sun, Nai-Yun
Chau, Gar-Yang
Fang, Wen-Liang
Chen, Ju-Pei
Wang, Hung-Ming
Hsieh, Meng-Che
Hua, Chun-Hung
Lien, Ming-Yu
Chang, Yi-Fang
Wang, Hui-Ching
Chien, Chih-Yen
Huang, Tai-Lin
Wang, Chen-Chi
Liu, Yi-Chun
Lu, Wei-Chen
Yiu, Ching-Yi
Lin, Chien-Liang
Chu, Pen-Yuan
Wang, Shao-Chun
Hung, Mien-Chie
Yang, Muh-Hwa
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.
Subjects
STAT1
acetylation
immune checkpoint blockade
inteferon gamma signaling
Type
journal article