{
  "abstract": "Background Cholangiocarcinoma (CCA), a malignancy arising from biliary epithelial cells, features a tumor microenvironment (TME) characterized by metabolic dysregulation and immunosuppression. Although diverse metabolic aberrations have been observed, the dominant metabolic driver remains unclear. Therefore, the study aims to elucidate the molecular connections between metabolic reprogramming and immune evasion, and to provide the basis for developing TME-targeted therapies.Methods First, untargeted metabolomics was performed to identify key metabolite classes involved in CCA progression. We subsequently used next-generation sequencing combined with database analysis to identify the key genes involved in tumor fatty acid metabolism. Metabolomics, proteomics and metabolic phenotyping experiments were subsequently performed to investigate this metabolic process. Tumor malignancy was evaluated using a range of in vitro and in vivo models. Single-cell RNA sequencing, Olink proteomics, flow cytometry and multiplex immunohistochemistry were performed to analyze the changes in the TME. Finally, we used humanized NOG mice to evaluate the efficacy of the combination therapy.Results Integrated multi-omics analysis revealed that long-chain unsaturated fatty acids (LCUFAs) were enriched in CCA tissues and closely associated with tumor progression. Ubiquitin-specific peptidase 1 (USP1) was upregulated in CCA tissues, driving dynamic lipid metabolic reprogramming and was associated with poor prognosis. Mechanistically, USP1 orchestrated LCUFAs accumulation through coordinating the enhancement of lipophagy and lipogenesis, establishing a systems-level metabolic regulatory network. Tumor-secreted LCUFAs were preferentially internalized by tumor-associated macrophages (TAMs) through FABP5, thereby suppressing cytotoxic T cells activity. Additionally, TAMs upregulated USP1 in CCA cells, forming a positive feedback loop that perpetuates the metabolic-immune crosstalk.Conclusion In summary, based on multi-omics analysis, this study establishes a systemic mechanism that links tumor lipid metabolism, immune suppression, and therapeutic response in CCA. Targeting the USP1-mediated metabolic-immune axis not only significantly suppresses tumor progression but also enhances the efficacy of immunotherapy. These findings construct a conceptual framework that integrates metabolic reprogramming, immune evasion, and treatment sensitivity, thereby establishing USP1 as a precision therapeutic target with broad biological and clinical importance for patients with CCA.",
  "authors": [
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China"
      ],
      "name": "Yananlan Chen"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Wuxi Medical Center of Nanjing Medical University, Wuxi People's Hospital, Wuxi, Jiangsu, China"
      ],
      "name": "Xiao Xu"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Shenye Shao"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Jiawei Zhang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Ziyang Wang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Changan Chen"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Wangjie Jiang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Jiang Chang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Ruixiang Chen"
    },
    {
      "affiliations": [
        "Jiangsu Province Hospital of Chinese Medicine, Nanjing, People's Republic of China"
      ],
      "name": "Tao Zhou"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Jifei Wang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Shuochen Liu"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Yue Yu"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Yaodong Zhang"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Changxian Li"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, Jiangsu, China",
        "Wuxi Medical Center of Nanjing Medical University, Wuxi People's Hospital, Wuxi, Jiangsu, China",
        "Nanjing Medical University, Nanjing, China",
        "NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Xiangcheng Li"
    }
  ],
  "title": "USP1-mediated lipophagy-lipogenesis axis drives cholangiocarcinoma progression and immune evasion",
  "uid": "d416924d-5281-5be4-bc45-47ce19d8ecc5"
}