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

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.