Identification of 2 Ubiquitin-Proteasome System-Related Subtypes in Esophageal Squamous Cell Carcinoma for Prognostic and Immunotherapeutic Response Prediction

Ubiquitin-proteasome system (UPS) is implicated in pathogenesis and progression of esophageal squamous cell carcinoma (ESCC), representing a promising therapeutic target. However, clinical significance of UPS in ESCC remains incompletely elucidated. UPS genes associated with ESCC survival were first screened through univariate Cox regression analysis. Consensus clustering was performed on TCGA-ESCC cohort based on these genes. Functional enrichment, tumor immune microenvironment analysis, and somatic mutation profiling were conducted for different clusters. Potential therapeutics and biomarkers were evaluated, and miRNA-TF-hub gene regulatory network was constructed. ESCC samples were stratified into 2 distinct clusters (cluster 1 and cluster 2), with cluster 1 demonstrating superior overall survival. Differential analysis revealed enrichment in cell adhesion and calcium signaling pathways. Immune infiltration analysis indicated elevated CD8+ T cells, mast cells, neutrophils, and TILs in cluster 2, alongside lower TIDE scores. TP53 exhibited the highest mutation frequency (93% vs. 86% in cluster 1 vs. cluster 2). Selumetinib, entinostat, and erlotinib were identified as candidate drugs for cluster 2, whereas tozasertib, alpelisib, and cediranib showed higher suitability for cluster 1. Ten potential biomarkers, 13 transcription factors, and 2 miRNAs were characterized. This study elucidates the role of UPS in ESCC progression and provides a framework for personalized treatment strategies.