{
  "abstract": "Background Steatotic liver disease-related hepatocellular carcinoma (SLD-HCC), a rising global challenge, is characterised by unique tumour microenvironment (TME) adaptations.Objective This study investigates the immune microenvironment and interactions driving immunosuppression and potential resistance to immunotherapy in SLD-HCC.Design We employed single-cell transcriptomics, cytometry by time-of-flight (CyTOF) and two independent spatial transcriptomics platforms to study the TME of 22 SLD-HCC and 31 non-SLD-HCC cases. Findings were further validated using multiplex immunohistochemistry in an independent cohort of 103 patients, an HCC model and an immunotherapy-treated patient cohort to evaluate clinical relevance.Results Our findings revealed significant alterations in immune and lipid metabolism pathways, particularly in regulatory T cells (Tregs) and cancer-associated fibroblasts (CAFs), suggesting distinct cellular adaptations to a high-fat TME and general immunosuppression. CyTOF revealed a cold, immunosuppressive TME with reduced CD8 + T cells and increased Tregs. Spatial transcriptomics further highlighted distinct Treg–CAF clusters localised at tumour margins, suggesting a spatially organised immunosuppressive niche. Mechanistically, tumour necrosis factor superfamily member 14 (TNFSF14)-tumour necrosis factor receptor superfamily member 14 (TNFRSF14)-mediated Treg–CAF interaction was identified as a critical driver of immunotherapy resistance in SLD-HCC. Blocking TNFRSF14 in an HCC model fed with a high-fat diet resulted in reduced Tregs, increased active CD8+ and memory CD4+ T cells, and a synergistic effect with anti-programmed cell death protein 1 therapy to enhance antitumour immunity and overcome immunotherapy resistance in SLD-HCC.Conclusion This study uncovers critical immune and metabolic adaptations in SLD-HCC, identifying TNFSF14-TNFRSF14 signalling as a key driver of immunotherapy resistance. Targeting this signalling axis enhances antitumour immunity and improves immunotherapy efficacy, offering a promising therapeutic strategy for SLD-HCC.",
  "authors": [
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Aldo Prawira"
    },
    {
      "affiliations": [
        "Binformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore"
      ],
      "name": "Hang Xu"
    },
    {
      "affiliations": [
        "Immunology Programme, Life Science Institute, Centre for Life Sciences, National University of Singapore, Singapore",
        "Department of Microbiology and Immunology, TRP Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Yu Mei"
    },
    {
      "affiliations": [
        "Department of Anatomical Pathology, Singapore General Hospital, Singapore"
      ],
      "name": "Wei Qiang Leow"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore",
        "Center for Computational Biology and Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore"
      ],
      "name": "Nurul Jannah Mohamed Nasir"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Marie JY Reolo"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Masayuki Otsuka"
    },
    {
      "affiliations": [
        "Division of Chronic Inflammation and Cancer, German Cancer Research Centre, Heidelberg, Germany",
        "M3 Research Center, Eberhard-Karls University Tübingen, Tübingen, Germany"
      ],
      "name": "Mohammad Rahbari"
    },
    {
      "affiliations": [
        "Division of Chronic Inflammation and Cancer, German Cancer Research Centre, Heidelberg, Germany",
        "M3 Research Center, Eberhard-Karls University Tübingen, Tübingen, Germany"
      ],
      "name": "Ziyao Chen"
    },
    {
      "affiliations": [
        "Immunology Programme, Life Science Institute, Centre for Life Sciences, National University of Singapore, Singapore",
        "Department of Microbiology and Immunology, TRP Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Madhushanee Weerasooriya"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Liyana Bte Abdullah"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Jiawei Wu"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Sharifah N Hazirah"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Martin Wasser"
    },
    {
      "affiliations": [
        "Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre, Singapore",
        "Singhealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore"
      ],
      "name": "Alexander Chung"
    },
    {
      "affiliations": [
        "Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre, Singapore",
        "Singhealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore"
      ],
      "name": "Brian KP Goh"
    },
    {
      "affiliations": [
        "Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital and National Cancer Centre, Singapore",
        "Singhealth-Duke-NUS Academic Surgery Program, Duke-NUS Graduate Medical School, Singapore",
        "Program in Clinical and Translational Liver Cancer Research, Division of Medical Science, National Cancer Center, Singapore"
      ],
      "name": "Pierce KH Chow"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Salvatore Albani"
    },
    {
      "affiliations": [
        "Division of Medical Oncology, National Cancer Centre Singapore, Singapore"
      ],
      "name": "Joycelyn Lee"
    },
    {
      "affiliations": [
        "Department of Anatomical Pathology, Singapore General Hospital, Singapore"
      ],
      "name": "Tony Kiat Hon Lim"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore",
        "State Key Laboratory of Animal Biodiversity Conservation and Integrated Pest, Chinese Academy of Sciences, Beijing, China",
        "Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunan, China"
      ],
      "name": "Weiwei Zhai"
    },
    {
      "affiliations": [
        "Division of Gastroenterology & Hepatology, Department of Medicine, National University Hospital, Singapore",
        "Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Yock Young Dan"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore"
      ],
      "name": "George BB Goh"
    },
    {
      "affiliations": [
        "Division of Chronic Inflammation and Cancer, German Cancer Research Centre, Heidelberg, Germany",
        "M3 Research Center, Eberhard-Karls University Tübingen, Tübingen, Germany"
      ],
      "name": "Mathias F Heikenwälder"
    },
    {
      "affiliations": [
        "Immunology Programme, Life Science Institute, Centre for Life Sciences, National University of Singapore, Singapore",
        "Department of Microbiology and Immunology, TRP Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Yongliang Zhang"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore",
        "Cancer Research UK (CRUK) Scotland Institute, Glasgow, UK"
      ],
      "name": "Ramanuj Dasgupta"
    },
    {
      "affiliations": [
        "Division of Medical Oncology, National Cancer Centre Singapore, Singapore"
      ],
      "name": "Wai Meng David Tai"
    },
    {
      "affiliations": [
        "Immunology Programme, Life Science Institute, Centre for Life Sciences, National University of Singapore, Singapore",
        "Department of Microbiology and Immunology, TRP Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Haiyan Liu"
    },
    {
      "affiliations": [
        "Binformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore",
        "Center for Computational Biology and Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore",
        "Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore",
        "Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Jinmiao Chen"
    },
    {
      "affiliations": [
        "Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore"
      ],
      "name": "Valerie Chew"
    }
  ],
  "title": "Targeting Treg–fibroblast interaction to enhance immunotherapy in steatotic liver disease-related hepatocellular carcinoma",
  "uid": "4e1dcfe7-0810-5956-8815-f911859938ef"
}