PTGDS deficiency as a driver of M2 macrophage polarization and immunosuppressive microenvironment in esophageal...

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.

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.

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.

PTGDS deficiency promotes immunosuppressive TME remodeling and predicts unfavorable clinical outcomes in ESCC, which might be a potential prognostic biomarker in ESCC.