Multiomics profiling reveals the prognostic significance and biological functions of the desmoglein family in cervical squamous cell carcinoma

While Desmoglein-2 (DSG2) is implicated in cervical cancer (CC) progression, its role in shaping the tumor immune microenvironment (TIME) remains elusive. This study leverages multi-omics data to delineate the oncogenic and immunomodulatory functions of DSG2 in cervical squamous cell carcinoma (CESC). We analyzed transcriptomic data from TCGA-CESC and validated findings in clinical specimens. We performed comprehensive immune infiltration analyses and evaluated correlations with immune checkpoints. Functional assays using DSG2-modulated HeLa cells assessed proliferation, migration, and invasion. Mechanistic insights were gained through Western blotting of the PI3K/AKT pathway. DSG2 was significantly overexpressed in CESC and served as an independent prognostic factor (HR = 1.833, 95% CI: 1.136–2.959). Crucially, high DSG2 expression correlated with an “immune-desert” TIME, characterized by specific immune cell alterations (e.g., Th2 cells lack effective T cell activation) and significant negative correlations with key immune checkpoint molecules (CTLA-4, PD-1, TIGIT, LAG-3). Functional enrichment analysis linked DSG2 to PI3K-Akt signaling and cell adhesion. In vitro, DSG2 enhanced HeLa cell malignancy, which is potentially coupled with PI3K/AKT pathway activation. Our study unveils DSG2 as a critical regulator of tumor progression and immune evasion in CESC. By integrating immune context with mechanistic exploration, we provide a more comprehensive understanding than prior studies that primarily focused on DSG2’s prognostic value and basic oncogenic functions without delving into immune interactions or the PI3K/AKT axis. DSG2 represents a promising dual-target for anti-tumor and immunotherapy-sensitizing strategies.