Endoplasmic Reticulum Stress-Driven LncRNA Signature Predicts Cervical Cancer Prognosis and Guides Personalized Immunotherapy: A Multi-Omics and Functional Validation Study

Abstract Endoplasmic reticulum (ER) stress is a key driver of tumor progression and therapeutic resistance. However, the prognostic role of ER stress-related long non-coding RNAs (lncRNAs) in cervical cancer has not been systematically elucidated. In this study, an ER stress-related lncRNA signature was constructed to evaluate patient prognosis and therapeutic responsiveness. Transcriptomic datasets derived from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project were integrated, leading to the identification of 197 ER stress-associated differentially expressed genes (DEGs) and 1,077 co-expressed lncRNAs. A prognostic 8-lncRNA model was developed using univariate/multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. The model was validated by survival analysis (Kaplan-Meier and receiver operating characteristic [ROC] curves), immune infiltration profiling (CIBERSORT and single-sample gene set enrichment analysis [ssGSEA]), and drug sensitivity analysis. Patients classified into the high-risk category showed significantly shorter overall survival (log-rank p < 0.001) and higher chemosensitivity to PI3K/mTOR inhibitors, whereas the low-risk group showed high immune activity (CD8+ T-cell infiltration and checkpoint expression) along with improved responsiveness to Wnt pathway inhibitors. The predictive capacity of the model (area under the curve, AUC: 0.806-0.856) exceeded that of conventional clinical parameters. Functional validation further revealed that LIPE-AS1, a representative high-risk lncRNA, promotes cervical cancer cell proliferation, migration, and invasion. These results introduce a novel ER stress-associated lncRNA signature with prognostic and therapeutic value, thus providing a potential basis for personalized immunotherapeutic and chemotherapeutic strategies in cervical cancer.