{
  "abstract": "Background Metabolites sculpt the immunosuppressive tumor microenvironment (TME) that facilitates immune evasion. As a crucial signaling lysophospholipid, lysophosphatidylserine (LysoPS) correlates with advanced disease stages in multiple tumor types. However, the mechanisms by which LysoPS drives gastric cancer peritoneal metastasis remain undefined.Methods Single-cell transcriptomic profiling of primary tumors, normal peritoneum, and metastatic lesions delineated mechanisms underlying LysoPS-mediated tumor-associated macrophages (TAMs) reprogramming. Immunohistochemistry and multiplex immunofluorescence validated GPR34-high TAMs infiltration in peritoneal metastases. Functional validation was performed using molecular assays and in vivo models.Results LysoPS accumulated in ascites from patients with gastric cancer peritoneal metastasis, establishing an immunosuppressive TME that drove malignant progression. Using single-cell transcriptome sequencing, we identified a distinct subset of TAMs highly expressing GPR34 enriched in gastric cancer peritoneal metastases, which correlates with tumor progression and immune evasion. Mechanistically, LysoPS engagement of GPR34 activated ERK/c-Jun signaling, transcriptionally upregulating AXL and CD36 to enhance efferocytosis. This effect drove TAMs toward an immunosuppressive phenotype, characterized by enhanced interleukin-10 and transforming growth factor-β secretion. GPR34 inhibitor attenuated M2-like TAMs infiltration while bolstering cytotoxic T cells recruitment and curtailing programmed cell death protein 1 (PD-1)+T cells accumulation. Furthermore, combination with anti-PD-1 therapy synergistically suppressed tumor growth beyond monotherapy efficacy.Conclusions LysoPS-GPR34 axis synergized with efferocytosis to amplify TAMs immunosuppressive properties, fostering an immune-evasive microenvironment; GPR34 inhibitor thus represents a promising strategy to potentiate PD-1 blockade efficacy in gastric cancer peritoneal metastasis.",
  "authors": [
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Jialong Lv"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Mingyue Zhang"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Fan Xiang"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Cheng Huang"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Dianshi Wang"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Kun He"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Guanxin Wei"
    },
    {
      "affiliations": [
        "Department of Critical Care Medicine, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Xiang Chen"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Danzeng He"
    },
    {
      "affiliations": [
        "The Sixth Hospital of Wuhan Affliated Hospital of Jianghan University, Wuhan, Hubei, China"
      ],
      "name": "Wenhao Wen"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China",
        "Department of Gastrointestinal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Kaixiong Tao"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Huazhong University of Science and Technology Tongji Medical College Union Hospital, Wuhan, Hubei, China"
      ],
      "name": "Chuanqing Wu"
    }
  ],
  "title": "LysoPS-GPR34 axis enhances tumor-associated macrophages efferocytosis to promote immune escape in gastric cancer peritoneal metastasis",
  "uid": "377c030c-2a3b-5b80-b847-112e8e6dc5e2"
}