HLA-DR+ Schwann Cells Generate the Protumor Cancer-Neuron-Immune Niche in Head and Neck Squamous Cell Carcinoma

  • Adv Sci (Weinh). 2026 Jun 15:e76131. doi: 10.1002/advs.76131.
Xiaoyan Meng  1 ,  Zhonglong Liu  1 ,  Shijian Zhang  1  2  3 ,  Luoman Gan  1 ,  Liren Cao  1 ,  Jingjing Sun  4 ,  Lingfang Zhang  5 ,  Yue He  1
Affiliations
  • 1. Department of Oral Maxillofacial & Head and Neck Oncology, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China.
  • 2. Department of Oral and Maxillofacial Surgery, Zhang Zhiyuan Academician Workstation, Hainan Province Clinical Medical Center For Stomatology, Hainan Western Central Hospital, Shanghai Ninth People's Hospital, Danzhou, Hainan, P. R. China.
  • 3. Department of Oral and Maxillofacial Head and Neck Oncology, Fengcheng Hospital of Shanghai Ninth People's Hospital Group, Shanghai, P. R. China.
  • 4. Department of Oral Pathology, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China.
  • 5. Suzhou Lingdian Biotechnology Co., Ltd, Suzhou, P. R. China.
PMID: 42295734 DOI: 10.1002/advs.76131
Abstract

Neural structures are widely distributed in the oral and maxillofacial region and play important roles in the progression of head and neck squamous cell carcinoma (HNSCC). Herein, we delineate the dynamic transition trajectory of Schwann cells during Cancer initiation and progression and identify a Schwann cell subpopulation, HLA-DR+ Schwann cell, that induced by Cancer cells and enriched as HNSCC progression. With the in vitro coculture assay and a Schwann cell-targeted gene engineering in vivo model, we demonstrate that Schwann cells are educated by HNSCC cells via the NRG1/ERBB3 axis, activate the downstream JAK/STAT signaling pathway, and acquire immunoregulatory and protumor phenotypes. Furthermore, HLA-DR+ Schwann cells are found to secrete CCL2 to induce a protumor macrophage subpopulation (Il1β. Mph), which promotes CD4+ T cell accumulation via CXCL10/CXCR3 for HLA-DR+ Schwann cells and assists them in shaping the cancer-neuron-immune niche and facilitating HNSCC progression. The tumor suppression effects of CCL2 inhibitor (Pirfenidone) and CXCR3 Inhibitor (AMG487) are validated in the orthotopic tumor model. Our findings reveal the mechanism of how HLA-DR+ Schwann cells generate cancer-neuron-immune niche, provide insights into tumor neurology, and lay foundations for therapeutics development for HNSCC patients.

Keywords
Il1β. macrophages; Tregs; head and neck squamous cell carcinoma; schwann cells; single‐cell RNA sequencing; tumor microenvironment.
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