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journal article·2026-06-15Open access

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

Xiaoyan Meng, Zhonglong Liu, Shijian Zhang, Luoman Gan, Liren Cao, Jingjing Sun, Lingfang Zhang, Yue He

Advanced Science
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Abstract

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.
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Research context

OpenAlex topics: Cancer, Stress, Anesthesia, and Immune Response · Cancer Immunotherapy and Biomarkers · Chemokine receptors and signaling

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

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

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

Department of Oral and Maxillofacial Head and Neck Oncology Fengcheng Hospital of Shanghai Ninth People′s Hospital Group Shanghai P. R. China

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

Suzhou Lingdian Biotechnology Co., Ltd Suzhou P. R. China

Funding

National Natural Science Foundation of China

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