Dynamic urinary proteomics integrates single-cell and spatial transcriptomics to reveal tumour microenvironment and predict immunotherapy response in biliary tract cancer

作者：Shanshan Wang, Zhengguang Guo, Boyu Sun, Kai Liu, Jiashuo Chao, Ziyu Xun, Yunchao Wang, Zibo Xu, Ziyue Huang, Hao Wang, Tan Yang, Tan Yang, Nan Zhang, Mingjian Piao, Longhao Zhang, Shuofeng Li, Shuofeng Li, Jiongyuan Li, Haidan Sun, Feng Qi, Xiaobo Yang, Xiaobo Yang, Chengpei Zhu, Hanping Wang, Hanping Wang, Wei Sun, Haitao Zhao · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-335513 · 被引用次数：2 · 研究领域：Cholangiocarcinoma and Gallbladder Cancer Studies、Single-cell and spatial transcriptomics、Cancer Immunotherapy and Biomarkers

BACKGROUND: Most patients with biliary tract cancer (BTC) do not derive durable clinical benefit (DCB) from immune checkpoint inhibitors (ICIs), underscoring the urgent need for predictive biomarkers. While urinary proteomics represents a non-invasive approach for biomarker discovery and mechanism exploration, its utility in ICI-treated patients with cancer remains unexplored. OBJECTIVE: We aimed to establish urinary proteomics as a predictive tool for ICI responsiveness and to elucidate its relationship with tumour dynamics and tumour microenvironment (TME) remodelling in BTC. DESIGN: We performed a staged mass spectrometry (MS)-based discovery-validation proteomics workflow in 211 urine samples from 97 treatment-naïve patients with BTC undergoing ICI-based therapy. A machine learning model was developed based on baseline proteomic features for ICI response prediction. Single-cell transcriptomics of 11 pretreatment tumour biopsies and spatial transcriptomics were integrated to explore the link between urinary proteomics and TME. RESULTS: Patients achieving DCB exhibited enrichment of immune activation and systemic inflammatory pathways, whereas non-durable benefit was correlated with protumourigenic processes. Longitudinal urinary proteomic dynamics could mirror TME remodelling and tumour evolution. A machine learning-derived 4-urinary protein panel (protein tyrosine phosphatase non-receptor 13 (PTPN13), SUB1, MICAL-L1, VARS1) robustly predicted DCB and early responses. Subs...