{
  "abstract": "Background Tumor-associated macrophages (TAMs) are abundant in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) and undergo metabolic reprogramming to support an immunosuppressive phenotype. While G protein-coupled receptors are known sensors of environmental cues, the specific role of the inhibitory G protein subunit alpha i3 (Gαi3) in linking metabolic stress to TAMs-mediated immunosuppression remains undefined.Methods Clinical associations were evaluated by multiplex immunohistochemistry, Kaplan-Meier analysis, and multivariable Cox regression. Myeloid-specific Gnai3-deficient mice were studied in DEN/CCl4 or DEN/HFD-induced and orthotopic HCC models. Metabolic reprogramming was assessed by targeted metabolomics, Seahorse analysis, and pharmacological inhibition of fatty acid oxidation. Mechanistic studies included co-immunoprecipitation, a cell-free kinase assay using recombinant AMPK and Gαi3, chromatin immunoprecipitation, promoter-reporter assays, cycloheximide-chase analysis, surface-biotinylation-based EGFR recycling assays, and GBF1 knockdown/rescue experiments.Results Gαi3 was upregulated in TAMs within glucose-deprived HCC regions and was associated with M2-like polarization, CD8+T cell exhaustion, and shorter overall survival. High TAM Gαi3 remained associated with overall survival after adjustment for clinical covariates. Myeloid-specific Gnai3 deletion suppressed HCC progression and restored cytotoxic CD8+T cell activity. Etomoxir phenocopied Gnai3 deficiency and attenuated macrophage-mediated T-cell suppression, supporting a requirement for fatty acid oxidation. Mechanistically, glucose deprivation activated AMPK-dependent phosphorylation of Gαi3; the cell-free kinase assay, mass spectrometry, and S143A mutagenesis together supported Ser143 as the relevant regulatory site. Active Gαi3 stabilized EGFR through a GBF1-associated trafficking program, promoted EGFR-dependent PKM2 nuclear translocation, and enhanced formation of a nuclear PKM2/HIF-1α transcriptional complex that activated Pparg and sustained an immunosuppressive fatty acid oxidation program.Conclusions Our study identifies Gαi3 as a critical metabolic checkpoint that orchestrates TAMs immunosuppression in the glucose-deprived TME. The Gαi3-EGFR-PKM2-PPARγ signaling axis drives metabolic reprogramming towards lipid oxidation, thereby inhibiting antitumor immunity. Targeting Gαi3 represents a novel immunotherapeutic strategy to reverse TAMs-mediated immunosuppression and improve outcomes in HCC.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China",
    "MOE Innovation Center for Basic Research in Tumor Immunotherapy, and Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China",
    "Medical School of Nanjing University, Nanjing, China",
    "Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China",
    "Department of Thoracic Surgery, Northern Jiangsu People’s Hospital, Yangzhou, Jiangsu, China",
    "Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
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        0,
        1
      ],
      "name": "Meixi Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yaoyao Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Siyu Du"
    },
    {
      "affs": [
        0
      ],
      "name": "Senlin Lian"
    },
    {
      "affs": [
        2
      ],
      "name": "Jiajing Luo"
    },
    {
      "affs": [
        3
      ],
      "name": "Yi Fang"
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    {
      "affs": [
        0
      ],
      "name": "Yangyang Jin"
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    {
      "affs": [
        4
      ],
      "name": "Mingjun Gao"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaowei Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Minghui Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Jie Wang"
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    {
      "affs": [
        0
      ],
      "name": "Yuanhong Xu"
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    {
      "affs": [
        2,
        5
      ],
      "name": "Chao Jiang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Runqiu Jiang",
      "orcid": "0000-0002-6995-9557"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/92nez6hfxg6mx.bib",
  "cited_by": 0,
  "doi": "10.1136/jitc-2026-015875",
  "fulltext_url": "https://jitc.bmj.com/content/14/10/e015875.full",
  "id": "92nez6hfxg6mx",
  "issns": [
    "2051-1426"
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  "landing_url": "https://doi.org/10.1136/jitc-2026-015875",
  "language": "en",
  "licence": "CC-BY-NC-4.0",
  "licence_label": "CC BY-NC 4.0",
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  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
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  "native_subjects": [
    [
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      "1506"
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    [
      "heading",
      "Basic and Translational Cancer Immunology"
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      "heading",
      "Original Research"
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      "lcc",
      "RC254-282"
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      "openalex",
      "2403|Immune cells in cancer"
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  "openalex": "W7224855146",
  "pdf_url": null,
  "pmcid": "PMC13723927",
  "pmid": "42963103",
  "published": "2026-10-30",
  "publisher": "BMJ Publishing Group",
  "ris": "https://research.draconitic.com/paper/92nez6hfxg6mx.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T14:22:50Z",
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  "subjects": [
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      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
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  ],
  "title": "Gαi3 acts as a metabolic checkpoint orchestrating TAMs immunosuppression and lipid metabolism in glucose-deprived hepatocellular carcinoma",
  "title_text": "Gαi3 acts as a metabolic checkpoint orchestrating TAMs immunosuppression and lipid metabolism in glucose-deprived hepatocellular carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:39Z",
  "url": "https://research.draconitic.com/paper/92nez6hfxg6mx",
  "venue": "Journal for ImmunoTherapy of Cancer",
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}