{
  "abstract": "Background The hepatocellular carcinoma (HCC) immune microenvironment is heavily influenced by immunosuppressive neutrophils, yet the mechanisms driving their senescence-associated reprogramming remain elusive.Objectives To elucidate the role of Selenoprotein P (Sepp1)-mediated selenium metabolism in driving the accumulation and immunosuppressive function of senescent-like neutrophils in HCC, and its impact on tumour immune evasion.Design We performed integrative single-cell RNA sequencing analyses in HCC mouse models, coupled with functional, metabolic and epigenetic assays to characterise neutrophil subpopulations and dissect the regulatory pathways linking Sepp1 and selenium metabolism to neutrophil senescence-associated reprogramming and tumour progression.Results We identified a distinct subpopulation of senescent-like tumour-infiltrating neutrophils marked by hepatic depletion of Sepp1, elevated Cdkn1a, S100a8/9 and Vegfa. Loss of tumour-derived Sepp1 impaired selenium uptake via Lrp8-mediated transport, suppressing intracellular selenium metabolism and hydrogen selenide production. This led to S-adenosylmethionine accumulation and increased histone H3 protein of trimethylation of lysine 4 histone modification, driving a prosenescence chromatin landscape. Selenium supplementation reversed these effects, restoring Sepp1 expression, reducing neutrophil senescence-associated reprogramming and reinvigorating anti-tumour immunity. Moreover, selenium synergised with anti-programmed cell death 1 therapy to suppress tumour growth.Conclusions Sepp1 is a key regulator of neutrophil senescence-associated reprogramming and immune suppression in HCC through selenium-dependent epigenetic remodelling. Targeting senescent-like neutrophils via selenium supplementation holds therapeutic promise to enhance immunotherapy efficacy in liver cancer.",
  "authors": [
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Jiazheng Jiao"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Lele Song"
    },
    {
      "affiliations": [
        "Department of Surgery, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, Hangzhou, China"
      ],
      "name": "Shengjun Xu"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Yuan Xue"
    },
    {
      "affiliations": [
        "State Key Laboratory of Regional and Urban Ecology, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China"
      ],
      "name": "Yanyan Liao"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Keying Xu"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Qian Wen"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Kai Xiang"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Rongrong Chen"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Xiaoxia Dong"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Weiwei Ji"
    },
    {
      "affiliations": [
        "State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, Shanghai, China"
      ],
      "name": "Yinlong Guo"
    },
    {
      "affiliations": [
        "Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital, Changhai Hospital, Naval Medical University, Shanghai, Shanghai, China"
      ],
      "name": "Gang Li"
    },
    {
      "affiliations": [
        "First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China"
      ],
      "name": "Haibiao Bao"
    },
    {
      "affiliations": [
        "Hepatobiliary Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Xiao Xu"
    },
    {
      "affiliations": [
        "Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Xuhui, Shanghai, China"
      ],
      "name": "Lixing Zhan"
    }
  ],
  "title": "Selenoprotein P deficiency drives hepatocellular carcinoma progression via induction of neutrophil senescence and immunosuppressive microenvironment",
  "uid": "2be93874-4cee-5e92-85cc-3eff82294f3f"
}