{
  "abstract": "Background Dietary fat promotes colorectal cancer, yet its impact on radiotherapy (RT) efficacy remains unclear. We investigated how a high-fat diet (HFD) modulates gut microbiota, metabolites and immune microenvironment to induce radiation resistance in rectal cancer.Methods Mice with orthotopic rectal tumors were fed an HFD or a control diet, with or without antibiotics. RT was delivered at 24 Gy in 3 fractions. Fecal microbiota transplantation (FMT) from HFD+RT mice to antibiotic-treated recipients validated causal effects. Gut microbiota and metabolites were analyzed by shotgun metagenomics and liquid chromatography-mass spectrometry. Tumor immune microenvironment was assessed by flow cytometry and immunofluorescence.Results HFD impaired RT efficacy, increasing tumor volume, pathological scores, and cellular proliferation; antibiotic treatment mitigated these effects. HFD induced gut microbial dysbiosis, including enrichment of Fusobacterium ulcerans and Fusobacterium gastrosuis and depletion of Bifidobacterium animalis. Metabolomics revealed upregulated bile acid biosynthesis, notably elevated taurochenodeoxycholic acid (TCDCA), with decreased hydantoin-5-propionic acid and indole-2-carboxylic acid. HFD suppressed IFN-γ + CD8+ T cells infiltration in tumor microenvironment, indicating impaired antitumor immunity; antibiotics partially restored their infiltration. FMT from HFD+RT mice recapitulated radiation resistance and CD8+ T cell suppression. Mechanistically, TCDCA promoted colorectal cancer cell proliferation and tumor growth post-RT in vitro and in vivo, reducing radiosensitivity. Moreover, in vitro, TCDCA impaired CD8+ T cell cytotoxicity with decreased levels of IFN-γ and granzyme B. Transcriptomic analysis revealed TCDCA suppressed type II interferon (IFN-γ) signaling in tumors. Depletion of CD8+ T cells attenuated TCDCA-mediated radioresistance in vivo, demonstrating dependence on CD8+ T cell–mediated immunity.Conclusions HFD induces gut microbiota dysbiosis and lipid metabolic reprogramming, elevating TCDCA levels, suppressing IFN-γ–mediated CD8 + T cell antitumor immunity, and reducing radiosensitivity in rectal cancer. These findings provide a mechanistic rationale for integrating dietary and metabolic interventions with radiotherapy to enhance treatment efficacy.",
  "authors": [
    {
      "affiliations": [
        "Department of Radiation Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, China"
      ],
      "name": "Jia Yang"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, China"
      ],
      "name": "Lihong Liu"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, China"
      ],
      "name": "Qichun Wei"
    }
  ],
  "title": "IDDF2026-ABS-0287 High fat diet-elevated TCDCA suppresses CD8+ T cell immunity and drives radioresistance in rectal cancer",
  "uid": "c679d447-3337-5c67-94fa-ff9f525cddfa"
}