{
  "abstract": "Background Metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) has been reported to be less responsive to immune checkpoint inhibitors, which may be associated with metabolic reprogramming of tumour cells and abnormal tumour microenvironment.Objective Here, we aim to investigate the role of gluconeogenic enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in MASH-HCC and its interplay with the tumour microenvironment.Design Hepatocyte-specific phosphatase and tensin homologue ( Pten) and Pck1 biallelic knockout mice were established to induce MASH-HCC. Single-cell RNA sequencing and multiparametrical flow cytometry were performed to analyse the immune landscape alterations. Untargeted metabolomics was conducted to elucidate the hepatic metabolism dysregulation.Results PCK1 is downregulated in tumour tissues compared with adjacent non-cancerous tissues from patients with MASH-HCC. Hepatocyte-specific Pck1 knockout mice exhibited markedly increased tumorigenesis in dietary models and genetic models of spontaneous MASH-HCC, together with inhibited effector function of tumour-infiltrating CD8+ T cells. Mechanistically, PCK1 deficiency induces the accumulation of endogenous metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which can be taken up by CD8+ T cells and activate the p38 mitogen-activated protein kinase pathway by directly interacting with the BTB and CNC homology 1 transcription factor, ultimately leading to CD8+ T cells dysfunction. Notably, PCK1 restoration or 12-HETE inhibition combined with anti-PD-1 treatment increases the antitumour capability of CD8+ T cells and suppresses MASH-HCC development.Conclusion This study reveals the pivotal role of the hepatic cell-intrinsic enzyme PCK1 in mediating CD8 + T cell dysfunction via 12-HETE-p38 signalling in MASH-HCC. PCK1 could be a metabolic checkpoint to enhance the efficacy of anti-PD-1 immunotherapy in MASH-HCC.",
  "authors": [
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Kang Wu"
    },
    {
      "affiliations": [
        "Department of Laboratory Medicine, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China",
        "Key Laboratory of Tumor lmmune Regulation and lmmune Intervention, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Luo Li"
    },
    {
      "affiliations": [
        "Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Yi Liu"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Kai Wang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Jianghong Zheng"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Huijun Liang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Fengli Xu"
    },
    {
      "affiliations": [
        "Department of Pathology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Renming Liu"
    },
    {
      "affiliations": [
        "College of Pharmacy, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Chang Chen"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Luyi Huang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Haijun Deng"
    },
    {
      "affiliations": [
        "Key Laboratory of Tumor lmmune Regulation and lmmune Intervention, Chongqing Medical University, Chongqing, China",
        "Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Xiaojian Han"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"
      ],
      "name": "Shi Chen"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Zhirong Zhang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Xinyu Liu"
    },
    {
      "affiliations": [
        "Bishan Hospital of Chongqing Medical University, Chongqing, Chongqing, China"
      ],
      "name": "Qiang He"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Chongqing Medical University, Chongqing, China",
        "Western (Chongqing) Collaborative Innovation Center for Intelligent Diagnostics and Digital Medicine, Chongqing National Biomedicine Industry Base, Chongqing, China"
      ],
      "name": "Xiaosong Li"
    },
    {
      "affiliations": [
        "Key Laboratory of Tumor lmmune Regulation and lmmune Intervention, Chongqing Medical University, Chongqing, China",
        "Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China",
        "The First Affiliated Hospital of Chongqing Medical University, Chongqing, China"
      ],
      "name": "Aishun Jin"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Ailong Huang"
    },
    {
      "affiliations": [
        "Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China"
      ],
      "name": "Ni Tang"
    }
  ],
  "title": "PCK1 deficiency promotes MASH-HCC progression by 12-HETE-induced CD8+ T cell dysfunction",
  "uid": "63115bc9-251a-5ded-9a6c-d3be1f66e200"
}