Objective: This study aimed to develop and validate an adenosynergic prognostic signature for stratifying clinical outcomes and characterizing the tumor immune microenvironment in patients with EOC.
Materials and Methods: A retrospective bioinformatics analysis, complemented by experimental validation, was conducted. Adenosine signaling activity was quantified using ssGSEA, and key adenosynergic modules were identified using WGCNA. Prognostically significant adenosine-related genes (ARGs) were selected through LASSO Cox regression to construct a composite signature, which was then validated across multiple datasets. Functional enrichment analysis, immune infiltration estimation, and somatic alteration mapping were performed. In vitro validation in SK-OV-3 and A2780 cell lines included quantitative PCR, metabolic viability assays, scratch assays, and chamber-based invasion assessments.
Results: The blue module showed the strongest correlation with adenosine pathway activity. Nine independent prognostic ARGs were identified: 5 risk-associated genes (PIK3CG, VSIG4, MATK, PIEZO1, and RARRES1) and 4 protective genes (SELL, S1PR4, IL18BP, and CD40LG). The signature demonstrated robust time-dependent predictive accuracy for overall survival, with AUCs ranging from 0.62 at 1 year to 0.71 at 5 years (95% CI: 0.58–0.75 for 1 year, 0.63–0.71 for 3 years, and 0.67–0.75 for 5 years). High-risk patients exhibited significantly worse survival and inversely correlated CD8⁺ T-cell and macrophage infiltration (p<0.001), suggesting impaired antitumor immunity. Somatic mutation analysis revealed co-occurrence patterns such as FAT3-MGA and MUC16-CSMD3 in high-risk cases. Experimental validation confirmed elevated ARG expression in cancer cells, and VSIG4 silencing significantly inhibited proliferation, migration, and invasion.
Conclusion: This study establishes a novel prognostic signature for stratifying OC outcomes. The model quantifies immunosuppressive microenvironmental features and identifies clinically actionable targets, particularly VSIG4, to guide treatment in EOC.