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: This study aimed to comprehensively characterize the features, interactions, and clinical significance of POSTN + cancer-associated fibroblasts (CAFs) and APOE + 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: A total of 206,399 cells were obtained from 29 LSCC single-cell samples (Tumor=16, Normal=13) and POSTN + CAF/APOE + TAM gene sets were identified. POSTN + CAFs and APOE + 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: The POSTN + CAF/APOE + 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. Keywords: laryngeal squamous cell carcinoma, tumor microenvironment, POSTN, APOE, cancer-associated fibroblast, tumor-associated macrophage