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Peer-reviewedCC BY 4.0Advanced Science

GM‐CSF Promotes Neutrophil PD‐L1 Expression Through the VEGFR‐2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell Carcinoma

  • Fangxing Zhu1,2,3,4,5
  • Yuanhe You2,3,4,5
  • Yiyi Zhang3,4,5,6
  • Yibin Dai1
  • Xinyu Zhou2,3,4,5
  • Yong Fu7
  • Xi Lu3,4,5,8
  • Yingying Huang1
  • Zhihang Zhou1
  • Ronghui Xia3,4,5,6
  • Wutong Ju2,3,4,5
  • Zhaoqi Yuan9
2 more authors
  • Laiping Zhong1
  • Tongchao Zhao1,2,3,4,5,10
10 affiliations
  1. 1Oromaxillofacial Head and Neck Surgery Center for Oromaxillofacial Head and Neck Disorders Huashan Hospital Fudan University Shanghai China
  2. 2Department of Oral & Maxillofacial‐Head & Neck Oncology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  3. 3College of Stomatology Shanghai Jiao Tong University Shanghai China
  4. 4National Center for Stomatology National Clinical Research Center for Oral Diseases Shanghai China
  5. 5Shanghai Key Laboratory of Stomatology Shanghai Research Institute of Stomatology Shanghai China
  6. 6Department of Oral Pathology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  7. 7Nanjing Stomatological Hospital Affiliated Hospital of Medical School Institute of Stomatology Nanjing University Nanjing China
  8. 8Department of Endodontics Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  9. 9Department of Plastic and Reconstructive Surgery Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine Shanghai China
  10. 10Department of Oral & Maxillofacial‐Head & Neck Oncology Shanghai Second People's Hospital Shanghai China
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhu2026gmcsf,
  title = {{GM‐CSF Promotes Neutrophil PD‐L1 Expression Through the VEGFR‐2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell Carcinoma}},
  author = {Fangxing Zhu and Yuanhe You and Yiyi Zhang and Yibin Dai and Xinyu Zhou and Yong Fu and Xi Lu and Yingying Huang and Zhihang Zhou and Ronghui Xia and Wutong Ju and Zhaoqi Yuan and Laiping Zhong and Tongchao Zhao},
  journal = {Advanced Science},
  year = {2026},
  month = aug,
  doi = {10.1002/advs.76960},
  url = {https://doi.org/10.1002/advs.76960},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - GM‐CSF Promotes Neutrophil PD‐L1 Expression Through the VEGFR‐2/STAT6/CSF2 Signaling Axis in Oral Squamous Cell Carcinoma
AU  - Fangxing Zhu
AU  - Yuanhe You
AU  - Yiyi Zhang
AU  - Yibin Dai
AU  - Xinyu Zhou
AU  - Yong Fu
AU  - Xi Lu
AU  - Yingying Huang
AU  - Zhihang Zhou
AU  - Ronghui Xia
AU  - Wutong Ju
AU  - Zhaoqi Yuan
AU  - Laiping Zhong
AU  - Tongchao Zhao
PY  - 2026
DA  - 2026/08/06
JO  - Advanced Science
DO  - 10.1002/advs.76960
UR  - https://doi.org/10.1002/advs.76960
AB  - 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.
SN  - 2198-3844
ER  -