{
  "abstract": "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. Subsequent external validation in an independent cohort (n=24) using parallel reaction monitoring-MS further confirms its generalisability. PTPN13+ malignant cells were identified as key regulators of proapoptotic TME states, contributing to sustained ICI responsiveness.Conclusions This study pioneers the application of urinary proteomics in immuno-oncology, providing a non-invasive approach to predict and monitor ICI responsiveness, while offering mechanistic insights into TME dynamics in BTC.",
  "authors": [
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China",
        "Department of Gastrointestinal Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Shanshan Wang"
    },
    {
      "affiliations": [
        "Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China"
      ],
      "name": "Zhengguang Guo"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Boyu Sun"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Kai Liu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China"
      ],
      "name": "Jiashuo Chao"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Ziyu Xun"
    },
    {
      "affiliations": [
        "Organ Transplantation Center, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China"
      ],
      "name": "Yunchao Wang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Zibo Xu"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Ziyue Huang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Hao Wang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Yang Tan"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Nan Zhang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Mingjian Piao"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Longhao Zhang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Chengjie Li"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Shuofeng Li"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Jiongyuan Li"
    },
    {
      "affiliations": [
        "Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China"
      ],
      "name": "Haidan Sun"
    },
    {
      "affiliations": [
        "Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China"
      ],
      "name": "Feng Qi"
    },
    {
      "affiliations": [
        "Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China"
      ],
      "name": "Aiwei Wang"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "XiaoBo Yang"
    },
    {
      "affiliations": [
        "Department of General Surgery Center, Beijing Youan Hospital, Clinical Center for Liver Cancer, Capital Medical University, Beijing, China"
      ],
      "name": "Chengpei Zhu"
    },
    {
      "affiliations": [
        "Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Hanping Wang"
    },
    {
      "affiliations": [
        "Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China"
      ],
      "name": "Wei Sun"
    },
    {
      "affiliations": [
        "Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, China"
      ],
      "name": "Haitao Zhao"
    }
  ],
  "title": "Dynamic urinary proteomics integrates single-cell and spatial transcriptomics to reveal tumour microenvironment and predict immunotherapy response in biliary tract cancer",
  "uid": "60d87a7f-2709-5c45-8b82-1587fd10e3ea"
}