A POSTN+ CAF/APOE+ TAM Axis is Associated with Tumor Progression and Potential Immunotherapy Resistance in Laryngeal Squamous Cell Carcinoma

Background: Laryngeal squamous cell carcinoma (LSCC) is a prevalent malignancy of the head and neck, characterized by a complex tumor microenvironment (TME) that hinders the effectiveness of immunotherapy. Objective: tumor-associated macrophages (TAMs) within the LSCC TME through integrative multi-omics analysis. Methods: We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq data from the GEO and TCGA databases. Differential expression, functional enrichment, cell-cell communication, multiplex immunofluorescence, spatial colocalization, molecular docking, and survival analyses were performed, with independent validation in the IMvigor210 immunotherapy cohort. Results: TAMs were enriched in LSCC tissues, and associated with epithelial-mesenchymal transition (EMT) and M2 macrophage polarization, respectively. Cell-cell communication and spatial analyses revealed close bidirectional signaling and spatial colocalization between the two cell types. Multiplex immunofluorescence staining further confirmed their close spatial proximity. Molecular docking suggested a potential structural compatibility between POSTN and APOE. Bulk RNA-seq analysis showed that their co-enrichment correlated with poor prognosis and resistance to immunotherapy, which were further confirmed in pan-cancer datasets. Conclusion: TAM axis is cooperatively associated with aggressive tumor behavior in LSCC and shapes an immunosuppressive microenvironment. This cellular axis may serve as a potential biomarker and therapeutic target for predicting prognosis and responsiveness to immunotherapy in LSCC.