{
  "abstract": "Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly immunosuppressive tumor microenvironment, which features a dense desmoplastic stroma enriched with cancer-associated fibroblasts (CAFs) that collectively impede the efficacy of immunotherapies. Although oncolytic viruses (OVs) have demonstrated promising potential in eliciting antitumor immunity, the mechanisms by which stromal components modulate OV efficacy remain poorly understood.Methods To investigate the interplay between immune and stromal components in PDAC following OV treatment, we employed murine and patient-derived tumor models. We characterized immune cell populations using single-cell RNA sequencing and flow cytometry. Functional studies included the engineering of a next-generation oncolytic herpes simplex virus expressing FLT3 ligand, OX40 ligand, and interleukin-12 (IL-12), combined with CD40 agonist antibodies to restore dendritic cell (DC) function and enhance T-cell responses.Results We identified a novel immunosuppressive circuit wherein monocytes, sensing damage-associated molecular patterns and pathogen-associated molecular patterns from OV-infected tumor cells, secrete interleukin-1β. This, in turn, triggers IL-6 production by CAFs, creating an IL-6-rich milieu that impairs DC maturation and co-stimulatory signaling, thereby attenuating T cell-mediated antitumor immunity and restricting OV therapeutic efficacy. Importantly, combination therapy with the engineered OV and CD40 agonist antibodies restored DC functionality and elicited robust tumor-specific T-cell responses in both murine and patient-derived models.Conclusion Our findings reveal a previously unrecognized monocyte-CAF-DC axis that mediates resistance to OV therapy through IL-1β and IL-6-driven suppression of DC function in PDAC. This study provides a mechanistically informed and translationally promising approach to overcome stromal immune suppression, restore effective antitumor immunity, and improve therapeutic outcomes for patients with PDAC.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Fan Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Jingru Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China",
        "School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, China"
      ],
      "name": "Yuanke Li"
    },
    {
      "affiliations": [
        "Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China"
      ],
      "name": "Wei Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Yi Yang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Jie Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Minghui Han"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China",
        "The Chinese University of Hong Kong Faculty of Medicine, Hong Kong, China"
      ],
      "name": "Han Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China",
        "Clinical Center for Biotherapy&Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Feilong Zhou"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Wenxuan Ma"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Yi Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Zhaoyuan Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Jufeng Yu"
    },
    {
      "affiliations": [
        "School of Health Science & Biomedical Engineering, Hebei University of Technology, Tianjin, China"
      ],
      "name": "Zhen Zhao"
    },
    {
      "affiliations": [
        "Beijing Institute of Biological Products Company Limited and CNBG-Nankai University Joint Research and Development Center, Beijing, China"
      ],
      "name": "Li Deng"
    },
    {
      "affiliations": [
        "Institute of Transplantation Medicin, Tianjin First Central Hospital, Tianjin, China"
      ],
      "name": "Shiyu Liu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Yajuan Wan"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, China"
      ],
      "name": "Zhigang Zhao"
    },
    {
      "affiliations": [
        "Department of Lung Cancer Surgery, Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, China"
      ],
      "name": "Song Xu"
    },
    {
      "affiliations": [
        "Beijing Mabworks Biotech Co Ltd, Beijing, China"
      ],
      "name": "Jiangmei Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China"
      ],
      "name": "Youjia Cao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Frontiers Science Centre for Cell Responses, CNBG–Nankai University Joint Research and Development Center, Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, China",
        "Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China"
      ],
      "name": "Hongkai Zhang"
    }
  ],
  "title": "Oncolytic virus-induced IL-1β+ monocyte-IL-6+ CAF axis suppresses dendritic cell-mediated antitumor immunity in pancreatic cancer",
  "uid": "515a1d1b-12be-5031-9f3e-fac9c3714cfb"
}