IL-1α drives a tumor-stroma-neutrophil axis through inflammatory fibroblast activation in head and neck cancer

In head and neck squamous cell carcinoma (HNSCC), high tumor-associated neutrophil (TAN) density is a robust biomarker of poor prognosis. TANs predominantly localize to the stroma and their intratumoral density strongly correlates with adverse outcome. Here, we investigated how tumor-stroma communication regulates TAN recruitment, activation, and spatial organization. We identified interleukin-1α (IL-1α), released by viable or necrotic tumor cells, as an upstream signal that induces an inflammatory cancer associated fibroblast (iCAF)-like transcriptional program in patient-derived mesenchymal stromal cells (MSCs) of the oral cavity. IL-1α-stimulated MSCs secrete factors associated with neutrophil recruitment, survival, and function, together with mediators of extracellular matrix remodeling and angiogenesis. Notably, the IL-1α-induced iCAF-like transcriptional program closely resembles CAF subsets in HNSCC that are associated with poor clinical outcome. Functionally, conditioned media from IL-1α-stimulated MSCs promoted tumor growth and enhanced polymorphonuclear neutrophil survival, activation, trans-well migration and infiltration into spheroids, in vitro . In zebrafish xenografts, co-injection of IL-1α-overexpressing tumor cells and MSCs markedly amplified neutrophil infiltration. TCGA analysis demonstrated robust correlations between the IL-1α-induced MSC gene signature and neutrophil signatures across multiple TAN subsets in human HNSCC. Spatial analysis of HNSCC tissues showed that stromal regions adjacent to IL1A -positive tumor islets were enriched for CXCL8/CSF3 double-positive cells and exhibited increased TAN density, including higher frequencies of NE– and MPO-positive neutrophils. Collectively, these findings define an IL-1α-dependent tumor-stroma signaling circuit that links tumor inflammation to stromal remodeling and neutrophil infiltration in HNSCC. Abstract Figure Graphical abstract: IL-1α drives tumor-stroma communication and neutrophil recruitment in HNSCC . Here, we describe a mechanism in HNSCC that promotes high tumor-associated neutrophil (TAN) density, a biomarker associated with poor prognosis. Tumor-derived IL-1α activates stromal cells to adopt an inflammatory phenotype, resulting in the release of CXCL8, GM-CSF, and G-CSF to enhance neutrophil recruitment, activation, and survival. IL1A -positive tumor islets are surrounded by CXCL8/CSF3 -rich stroma with elevated TAN densities in both tumor and stromal compartments. These TANs exhibit increased frequencies of MPO– and NE-positive cells, revealing a spatially organized inflammatory tumor microenvironment. Figure was created using BioRender.