{
  "abstract": "Background Gastric cancer (GC) ranks among the most prevalent lethal tumours globally. Cancer-associated fibroblasts (CAFs) are pivotal in creating an immunosuppressive tumour microenvironment (TME) in GC.Objective Identifying a critical subpopulation of CAFs in promoting an immunosuppressive TME and enabling immune evasion, which may influence therapeutic effectiveness of immune checkpoint inhibitors (ICIs) for GC.Design We performed single-cell RNA sequencing on 24 patients with GC and spatial transcriptomic profiling on formalin-fixed paraffin-embedded tissue sections from patients and controls. Integrating these data, we mapped cell types and gene signatures and identified distinct CAF subpopulations in the TME that influenced immunotherapy response in patients with GC. In vitro and in vivo studies further elucidated the molecular mechanisms, enhancing therapeutic implications.Results In patients with GC, phosphodiesterase type 5A (PDE5A) expression was associated with shorter overall survival and the formation of immunosuppressive TME. We identified PDE5A + CAFs that were associated with TME alterations, including T cell exclusion and reduced CD8+ cytotoxic T lymphocyte infiltration, potentially impairing the efficacy of immunotherapy in GC. PDE5A+ CAFs were observed to promote the epithelial–mesenchymal transition of GC cells through remodelling extracellular matrix. Furthermore, PDE5A+ CAFs, via triggering of the PI3K/AKT/mTOR signalling pathway, released CXCL12, which engaged the CXCR4 receptor, consequently recruiting CD8+ TEX+ LAG3 T cells to facilitate the development of immunosuppressive TME. The combined treatment of LAG3 blockade and PDE5A inhibitor vardenafil effectively enhanced immunotherapy responses, significantly curbing GC progression in mouse models.Conclusions Our study elucidates the intricate role of PDE5A + CAFs in shaping the immunosuppressive TME in GC, providing mechanistic insights and therapeutic potential for combating this aggressive malignancy.",
  "authors": [
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China"
      ],
      "name": "Kewei Wang"
    },
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China",
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Chen-jun Xie"
    },
    {
      "affiliations": [
        "Department of General Surgery, Jiangnan University Affiliated Central Hospital, Wuxi, Jiangsu, China"
      ],
      "name": "Zheng Ding"
    },
    {
      "affiliations": [
        "Department of General Surgery, Jiangnan University Affiliated Central Hospital, Wuxi, Jiangsu, China"
      ],
      "name": "Ting Shan"
    },
    {
      "affiliations": [
        "Macao Centre for Research and Development in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China"
      ],
      "name": "Zhangfeng Zhong"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Feng-lai Yuan"
    },
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China"
      ],
      "name": "Jun-jie Wu"
    },
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China"
      ],
      "name": "Zheng-dong Yuan"
    },
    {
      "affiliations": [
        "Departments of Gastrointestinal Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China"
      ],
      "name": "Chengjia Qian"
    },
    {
      "affiliations": [
        "Departments of Gastroenterology, Affiliated Hospital of Jiangnan University, Wuxi, China"
      ],
      "name": "Lihua Yu"
    },
    {
      "affiliations": [
        "Departments of Pathology, Affiliated Hospital of Jiangnan University, Wuxi, China"
      ],
      "name": "Yankui Liu"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Jianqing Cheng"
    },
    {
      "affiliations": [
        "Departments of Gastroenterology, Nanjing Medical University Affiliated Wuxi People’s Hospital, Wuxi, Jiangsu, China"
      ],
      "name": "Qing-lin Zhang"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Wei Liu"
    },
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China",
        "Department of Thoracic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China"
      ],
      "name": "Yong Zhao"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China"
      ],
      "name": "Jianfeng Huang"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Wen-zhe Zhang"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Qian Yin"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Bo-yu Gao"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Jie-qing Hou"
    },
    {
      "affiliations": [
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Ji-chao Wang"
    },
    {
      "affiliations": [
        "The First Clinical Medicine College, Nanjing Medical University, Nanjing, Jiangsu, China"
      ],
      "name": "Jie Mei"
    },
    {
      "affiliations": [
        "Institute of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China",
        "Jiangnan University Wuxi Medical College, Wuxi, Jiangsu, China"
      ],
      "name": "Chao Deng"
    }
  ],
  "title": "PDE5A+ cancer-associated fibroblasts enhance immune suppression in gastric cancer",
  "uid": "ad8dd35d-30a4-5f78-b9d3-fee7f3e8f59d"
}