{
  "abstract": "Background Glucose restriction is a hallmark of the tumor microenvironment (TME), yet how tumor cells adapt to this metabolic stress and the impact of metabolic reprogramming on the TME remains incompletely understood.Methods A genome-wide CRISPR knockout positive screen was performed to identify key mediators of cellular adaptation to glucose restriction. Using biochemistry, molecular biology, metabolomics and confocal immunofluorescent microscopy to elucidate the underlying molecular mechanisms. Additionally, single-cell RNA sequencing and orthotopic tumor models were used to characterize TME remodeling and assess therapeutic efficacy.Results We identified zinc and ring finger 3 (ZNRF3) as a key mediator of cellular adaptation to glucose restriction through genome-wide CRISPR/Cas9 screening. Multiple tumor cells adaptively survived in glucose-restricted conditions with downregulated ZNRF3. Mechanistically, low glucose suppresses ZNRF3 expression, leading to Wnt pathway activation and subsequent transcriptional repression of stearoyl-CoA desaturase (SCD). This metabolic rewiring enhances antitumor immunity by increasing T-cell infiltration and cytotoxicity. In multiple preclinical models, dietary glucose restriction synergizes with immune checkpoint blockade to suppress tumor growth.Conclusion These findings establish the ZNRF3-Wnt-SCD axis as a metabolic checkpoint controlling tumor cell fate under glucose restriction and provide a rationale for combining dietary intervention with immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Yarui Ma"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Qi Zhang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Zhewen Wei"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Zhendiao Zhou"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xue Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Chungui Xu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Xiu Liu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Shitong Min"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Peng Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Fangqing Yuan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China",
        "Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Yuchen Jiao"
    },
    {
      "affiliations": [
        "Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China"
      ],
      "name": "Guangwen Yuan"
    }
  ],
  "title": "Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis",
  "uid": "c73ee689-fd0e-570f-9b08-a0b9246b44c7"
}