PSD3 as a context-dependent modulator of immune landscape and tumor aggressiveness in esophageal squamous cell carcinoma

In this study, we investigated PSD3, CD274 (PD-L1), and TNFSF18 as potential immune-related biomarkers in esophageal squamous cell carcinoma (ESCC) using integrative transcriptomic and experimental approaches. CD274 and TNFSF18 were consistently up-regulated in ESCC across both TCGA and GEO datasets, while PSD3 showed significantly higher expression in TCGA but no significant difference in the GEO cohort. Only PSD3 demonstrated a significant association with overall survival, with higher expression correlating with improved prognosis. Interestingly, despite its favorable prognostic value, PSD3 functionally promoted ESCC cell proliferation, invasion, and migration <i>in vitro</i>, while inversely regulating PD-L1 expression. Conversely, heterozygous knockout of PD-L1 in KYSE150 cells impaired tumor aggressiveness. Co-immunoprecipitation revealed a direct physical interaction between PSD3 and PD-L1, suggesting a regulatory axis with implications for immune evasion. These findings position PSD3 as a context-dependent immuno-oncogenic factor and a potential therapeutic target in ESCC.