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

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.