{
  "abstract": "Oral squamous cell carcinoma (OSCC) remains a highly aggressive malignancy with limited responsiveness to anti‐PD‐1 immunotherapy. Recent neoadjuvant studies combining VEGFR‐2 inhibition (VEGFR2i) with anti‐PD‐1 (aPD‐1) have yielded markedly improved pathological responses, suggesting a VEGFR‐2‐dependent immunoregulatory mechanism. Here, we identify a PD‐L1‐expressing CD66b+ neutrophil‐enriched tumor‐associated population as a critical immunosuppressive population enriched in VEGFR‐2‐high OSCC tumors and associated with increased metastatic propensity and inferior patient outcomes. Using multiplex immunohistochemistry, scRNA‐seq, and flow cytometry, we demonstrate that VEGFR‐2‐overexpressing OSCC cells drive robust GM‐CSF secretion, which in turn induces PD‐L1 upregulation in neutrophils. Mechanistically, VEGFR‐2 activation promotes STAT6 phosphorylation and nuclear translocation, enabling direct transcriptional activation of CSF2. GM‐CSF subsequently activates STAT5 and mTOR/S6K signaling in neutrophils, thereby enhancing PD‐L1 protein synthesis. Functionally, these PD‐L1+ TANs suppress CD8+ T‐cell proliferation, augment T‐cell exhaustion, and diminish cytotoxicity. Importantly, VEGFR‐2 inhibition or GM‐CSF neutralization restored CD8+ T‐cell function and improved responsiveness to anti‐PD‐1 therapy in vivo, whereas exogenous GM‐CSF impaired VEGFR2i/aPD‐1 efficacy. Collectively, our findings reveal a previously unrecognized VEGFR‐2/STAT6/CSF2 axis that licenses neutrophil‐mediated immune suppression in OSCC. These data provide mechanistic rationale and preclinical support for targeting the VEGFR‐2/GM‐CSF‐neutrophil axis to improve the efficacy of PD‐1 blockade in OSCC.",
  "abstract_shown": true,
  "affiliations": [
    "Oromaxillofacial Head and Neck Surgery Center for Oromaxillofacial Head and Neck Disorders Huashan Hospital Fudan University Shanghai China",
    "Department of Oral & Maxillofacial‐Head & Neck Oncology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China",
    "College of Stomatology Shanghai Jiao Tong University Shanghai China",
    "National Center for Stomatology National Clinical Research Center for Oral Diseases Shanghai China",
    "Shanghai Key Laboratory of Stomatology Shanghai Research Institute of Stomatology Shanghai China",
    "Department of Oral Pathology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China",
    "Nanjing Stomatological Hospital Affiliated Hospital of Medical School Institute of Stomatology Nanjing University Nanjing China",
    "Department of Endodontics Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China",
    "Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China",
    "Department of Oral & Maxillofacial‐Head & Neck Oncology Shanghai Second People's Hospital Shanghai China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Fangxing Zhu",
      "orcid": "0000-0001-8581-254X"
    },
    {
      "affs": [
        1,
        2,
        3,
        4
      ],
      "name": "Yuanhe You"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Yiyi Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yibin Dai",
      "orcid": "0009-0003-1080-4264"
    },
    {
      "affs": [
        1,
        2,
        3,
        4
      ],
      "name": "Xinyu Zhou"
    },
    {
      "affs": [
        6
      ],
      "name": "Yong Fu"
    },
    {
      "affs": [
        2,
        3,
        4,
        7
      ],
      "name": "Xi Lu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yingying Huang",
      "orcid": "0000-0003-0389-6423"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhihang Zhou"
    },
    {
      "affs": [
        2,
        3,
        4,
        5
      ],
      "name": "Ronghui Xia"
    },
    {
      "affs": [
        1,
        2,
        3,
        4
      ],
      "name": "Wutong Ju"
    },
    {
      "affs": [
        8
      ],
      "name": "Zhaoqi Yuan"
    },
    {
      "affs": [
        0
      ],
      "name": "Laiping Zhong"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4,
        9
      ],
      "name": "Tongchao Zhao",
      "orcid": "0000-0002-2525-9671"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4am7zk1hkmgca.bib",
  "cited_by": 0,
  "doi": "10.1002/advs.76960",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13445316/",
  "id": "4am7zk1hkmgca",
  "issns": [
    "2198-3844"
  ],
  "landing_url": "https://doi.org/10.1002/advs.76960",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7196953672",
  "pdf_url": null,
  "pmcid": "PMC13445316",
  "pmid": "42559673",
  "published": "2026-08-06",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/4am7zk1hkmgca.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:23:42Z",
      "native_id": "PMC13445316",
      "source": "pmc",
      "url": "https://doi.org/10.1002/advs.76960"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "GM‐CSF Promotes Neutrophil PD‐L1 Expression Through the VEGFR‐2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell Carcinoma",
  "title_text": "GM‐CSF Promotes Neutrophil PD‐L1 Expression Through the VEGFR‐2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell Carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:20:50Z",
  "url": "https://research.draconitic.com/paper/4am7zk1hkmgca",
  "venue": "Advanced Science",
  "versions": []
}