Multi-omics profiling reveals PIK3CA -driven immunometabolic reprogramming in cervical cancer

The PIK3CA mutation is a prevalent driver in cervical cancer, but its role in orchestrating a coordinated remodeling of transcriptional, translational, and metabolic networks is poorly understood. We introduced the PIK3CA-E545K mutation into cervical cancer U14 cells via CRISPR/Cas9 to generate an isogenic model. A comprehensive multi-omics approach was employed, including RNA sequencing, LC-MS/MS-based proteomics and metabolomics, followed by integrated bioinformatics and correlation network analysis. Functional validation was performed through Western blot, colony formation, CCK-8 proliferation, wound healing assays, and a subcutaneous mouse model. As expected from the established oncogenic function of activating PIK3CA mutations, PIK3CA-E545K enhanced cellular proliferation, clonogenicity, migratory capacity, and in vivo tumor growth, thereby validating the functional activity of the engineered isogenic model. Transcriptomic analysis revealed extensive immunoinflammatory dysregulation, with enrichment of pathways including cytokine–cytokine receptor interaction and JAK–STAT signaling. Proteomics identified 176 differentially abundant proteins, with hub nodes such as Cd44 and Flt1 central to a rewired interaction network and enrichment in metabolic processes including glycolysis and arginine/proline metabolism. Metabolomics demonstrated a profound metabolic shift characterized by global suppression of lipid biosynthesis pathways, including unsaturated fatty acid biosynthesis, together with elevated oxidative stress markers. Cross-omics integration further revealed coordinated alterations associated with lipid metabolism and redox-related processes, with key molecules including Cd44 and Smox showing consistent correlations from RNA or protein levels to metabolite abundance. Our integrated multi-omics analysis indicates that the PIK3CA mutation is associated with extensive alterations in immune-related and metabolic pathways in cervical cancer cells. This remodeling is primarily driven by concurrent suppression of lipid metabolism and exacerbation of oxidative stress, suggesting a potential mechanistic link between intracellular metabolic changes and pro-tumorigenic inflammatory signaling. The impact of these cell-intrinsic alterations on the tumor immune microenvironment warrants further investigation.