PTGDS deficiency as a driver of M2 macrophage polarization and immunosuppressive microenvironment in esophageal squamous cell carcinoma: an experimental study

Introduction: Esophageal squamous cell carcinoma (ESCC) exhibits poor survival linked to M2 macrophage-polarized microenvironment. This study aimed to elucidate the role of prostaglandin D2 synthase (PTGDS) in modulating tumor microenvironment (TME) and its prognostic implications in ESCC. Materials and methods: Transcriptomic datasets (GSE53624, GSE121931) were analyzed using immune deconvolution and weighted gene co-expression network analysis to identify genes associated with M2 macrophage infiltration. Differentially expressed genes between tumor and normal tissues were assessed in Gaozhou-RNA cohort. Cox regression analyses were conducted to evaluate prognostic factors. A nomogram incorporating PTGDS expression and clinicopathological parameters was developed and validated by immunohistochemistry (IHC) which was performed in the Gaozhou-IHC cohort. In vitro experiments were used to validate the role of PTGDS. Results: PTGDS expression was significantly downregulated in ESCC tissues and reduced PTGDS expression was identified as a significantly prognostic factor for worse overall survival (OS). A combined nomogram demonstrated strong predictive accuracy, with area under the curve (AUC) values of 0.63, 0.77, and 0.83 for 1-, 3-, and 5-year OS predictions in the GSE53624 cohort, which remained consistent across validation cohorts (GSE121931 and Gaozhou-IHC cohort). Lower PTGDS expression was significantly associated with increased myeloid-derived suppressor cells recruitment, reduced T cell infiltration, and impaired T cell cytotoxicity. IHC confirmed elevated CD206 + M2 macrophage infiltration in PTGDS-low tumors. In vivo and in vitro experiments further demonstrated PTGDS overexpression effectively suppressed M2 macrophage polarization. Conclusion: PTGDS deficiency promotes immunosuppressive TME remodeling and predicts unfavorable clinical outcomes in ESCC, which might be a potential prognostic biomarker in ESCC.