{
  "abstract": "Background Gut microbiota can modulate cancer immunotherapy and enhance the efficacy of programmed cell death protein 1 (PD-1) blockade in tumors, yet the responsible microbes and underlying mechanisms remain incompletely understood.Methods Publicly available anti-PD-1-treated melanoma microbiome cohorts were reanalyzed. Causal validation was performed using oral Blautia coccoides (B. coccoides) supplementation in B16-F10 melanoma-bearing mice. Untargeted and targeted liquid chromatography-tandem mass spectrometry-based metabolomics, CD8+ T-cell depletion, receptor identification and binding analyses, and downstream transcriptomic and biochemical assays were used to identify the key metabolite and investigate its mechanism of action.Results We identified Blautia as enriched in melanoma patients responding to immune checkpoint inhibitors, with higher abundance associated with non-progression. In melanoma-bearing mice, oral B. coccoides suppressed tumor growth and increased intratumoral effector CD8+ T cells. Metabolomic profiling identified acetate as a prominent B. coccoides-associated metabolite. Acetate enhanced CD8+ T-cell effector function. CD8+ T-cell depletion largely abrogated the antitumor effects of both B. coccoides and acetate, supporting a central role for CD8+ T cells. Mechanistically, these findings support a model in which acetate is associated with a TLR3-linked signaling pathway in CD8+ T cells, accompanied by PI3K/Akt activation and enhanced effector function. Notably, B. coccoides or acetate potentiated anti-PD-1 therapy in mouse melanoma models, supporting their potential as adjunctive strategies for melanoma immunotherapy.Conclusions These findings support a model of an acetate-TLR3-linked PI3K/Akt signaling axis linking microbiota-associated metabolites to CD8 + T cell-mediated antitumor immunity. Importantly, our study highlights both B. coccoides and its derivative, acetate, as preclinical adjunctive candidates to potentiate anti-PD-1 efficacy in melanoma.",
  "authors": [
    {
      "affiliations": [
        "Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Zhiwen Zhang"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Xiaofeng Liang"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Yuyang Tian"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Chengyi Li"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Xueli Cao"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Di Wang"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Ansheng Xie"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Siqi Liu"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Kefan Lin"
    },
    {
      "affiliations": [
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Qing Li"
    },
    {
      "affiliations": [
        "Hunan Key Laboratory of Medical Epigenomics & Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China",
        "The First School of Clinical Medicine, Southern Medical University",
        "Department of Dermatology, Dermatology Hospital, Southern Medical University, Guangzhou, Guangdong, China"
      ],
      "name": "Yunsheng Liang"
    }
  ],
  "title": "Blautia coccoides-derived acetate potentiates anti-PD-1 immunotherapy in melanoma by activating cytotoxic CD8+ T cells",
  "uid": "470bb9e9-f007-5b83-8d20-b004eaa22052"
}