Targeting MLCK1 uncouples immune checkpoint inhibitor-induced colitis from antitumour immunity

作者：Lei Xiong, Jianshang Huang, Yunsheng Dong, Wei Han, Wei-Ting Kuo, Wentao Xu, Yiran Han, Chenchen An, Rumeng Zhu, Nina Zhu, Hanqi Xia, Abduxukur Rahman, Sainan Tang, Chonggui Jiang, Junhao Zhao, Wangxiang Pei, Juan Wang, Xianda Wang, Jiayi Song, Zihan Wang, Shanshan Wu, Heng Zhang, Honghai Xu, Baoming Wu, Qiansheng Huang, Bin Bao, Qiao Mei, Huaqing Zhu, Lanlan Hou, Suthat Liangpunsakul, Feng Cao, H Weng, Bei Tan, J R Turner, Hua Wang, Li Zuo · 发表于：Gut · 年份：2026 · DOI：10.1136/gutjnl-2025-337780 · 被引用次数：4 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Barrier Structure and Function Studies

OBJECTIVE: Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment and patients' survival. However, ICIs also cause severe immune-related adverse events, notably colitis, resulting in ICIs therapy discontinuation and tumour immunotherapy failure. This study investigates long myosin light chain kinase 1 (MLCK1), a known regulator of tight junction and gut permeability, to elucidate the mechanisms underlying ICI-mediated colitis and identify approaches to reduce this toxicity. DESIGN: This study employed an integrated approach, using clinical samples, in vivo models and in vitro organoid systems. Biopsies from patients with ICIs colitis were profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. To recapitulate human ICIs colitis, we used a wild mouse microbiota (WildR) model, alongside various genetically modified and tumour-bearing models (including melanoma and MC38). Furthermore, mechanisms were investigated through organoid-immune cell co-cultures. Finally, surface plasmon resonance, microscale thermophoresis, full-spectrum flow cytometry, bulk RNA sequencing, immunostaining, ELISA and gut permeability assays were performed to comprehensively delineate the underlying molecular mechanism. RESULTS: T cells as an upstream regulator that induces colitis through this MLCK-dependent mechanism, as genetic deletion of MLCK preserved the tight junction structure and ameliorated the inflammation and ICIs colitis. Furthermore, a pharmacolo...