IL1B⁺ Tumor-associated macrophages arise from inflammatory cancer-associated fibroblasts niches and are correlated with head and neck squamous cell carcinoma recurrence

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are major components of the tumor microenvironment (TME), influencing tumor immunity, cancer progression, and treatment responses. Interactions between CAF and TAM subpopulations have only recently been investigated, revealing complex mechanisms that may shape tumor immunity and therapeutic outcomes. In this study, we performed single-cell RNA sequencing and spatial transcriptomics on primary patient-derived HPV-negative head and neck squamous cell carcinoma (HNSCC) tumors to characterize cellular heterogeneity and stromal-immune crosstalk. We identified five TAM and four CAF subsets, with IL1B + TAMs and IL-iCAFs forming a distinct, spatially co-localized inflammatory niche. In vitro co-culture experiments revealed that IL-iCAF-derived paracrine signals induced transcriptional features associated with the IL1B⁺ TAM state. Clinically, high infiltration of IL1B ⁺ TAMs correlated with poorer survival and higher recurrence risk, likely driven by increased inflammatory signaling from IL1B + TAMs that promotes regulatory T cell recruitment and exhaustion. Together, our findings identify a spatially organized inflammatory niche involving IL-iCAFs and IL1B ⁺ TAMs and suggest that fibroblast-derived signals may contribute to the acquisition of inflammatory TAM features. These findings provide a basis for further investigation of IL-iCAF–TAM interactions and the potential clinical relevance of IL1B ⁺ TAMs in HPV-negative HNSCC.