Low PTGDS Expression Facilitates HNSCC by Suppressing Programmed Cell Death and Reducing B Cell–Mediated Immune Responses

Head and neck squamous cell carcinoma (HNSCC) constitutes a significant global disease burden. Evasion of programmed cell death (PCD) is a hallmark of HNSCC progression. Cancer-associated fibroblasts (CAFs) are a major cellular component of the HNSCC tumor microenvironment (TME). However, the mechanism by which CAFs contribute to PCD resistance remains poorly understood. This study included 24 single-cell sequencing samples, the Cancer Genome Atlas (TCGA) data, and spatial transcriptome data from HNSCC samples. Single-cell data were clustered using the Seurat package, and pseudotemporal trajectory analysis of CAF subsets was performed with Monocle2. The random forest algorithm was used to assess the prognostic importance of candidate genes. The ssGSEA and CIBERSORT algorithms were used to assess immune cell infiltration patterns in the TCGA samples. Gain-of-function assays, Western blotting, and immunohistochemistry were conducted to validate the biological functions of key targets. Here, we identified seven CAF subsets and clarified their potential differentiation directions. Thirty-two CAF-associated PCD regulators with prognostic significance were identified, among which, prostaglandin D2 synthase (PTGDS) and squalene epoxidase (SQLE) are the most important genes. PTGDS is significantly downregulated in HNSCC and associated with favorable prognosis. PTGDS overexpression significantly inhibited clonogenicity, proliferation, and invasion while promoting apoptosis in HNSCC cells (p < 0.05). In addition, PTGDS expression is significantly enriched in B cell-related pathways. Mechanistically, PTGDS overexpression increased chemokine (C-X-C motif) ligand 13 (CXCL13) expression and enhanced immune cell infiltration. These findings identified PTGDS as a central regulator linking CAF-mediated PCD resistance and B cell immune modulation in HNSCC, suggesting its potential as both a diagnostic biomarker and therapeutic target.