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The Unfolded Protein Response (UPR) is a key adaptive stress pathway implicated in therapy resistance. To discover clinically actionable biomarkers, we employed an integrated multi\u2010omics strategy, combining single\u2010cell and bulk transcriptomic data from multiple glioma cohorts. Using hdWGCNA network analysis, we identified a UPR\u2010associated gene module that defined two molecular subtypes with stark survival differences. Through a rigorous machine learning pipeline (Random Survival Forest, LASSO, and CoxBoost), ANXA5 emerged as the central prognostic gene. High ANXA5 expression consistently predicted poorer overall survival across eight independent datasets, validating its robust prognostic value. Functionally, ANXA5 was linked to extracellular matrix remodeling and immune modulation. Multi\u2010omics profiling revealed that ANXA5\u2010high gliomas exhibit a T\u2010cell\u2010inflamed yet immunosuppressive TME, characterized by elevated immune checkpoint expression. Crucially, ANXA5 demonstrated strong predictive power for response to immune checkpoint blockade (ICB), showing significant correlation with nine established immunotherapy response signatures and accurately discriminating responders from non\u2010responders in six independent ICB\u2010treated clinical cohorts (AUC: 0.65\u20130.78). Genomic analysis associated ANXA5 expression with distinct mutation patterns (EGFR\/PTEN vs. IDH1\/TP53). In\u00a0vitro knockdown of ANXA5 confirmed its oncogenic role, as it suppressed glioma cell proliferation and invasion. Our study establishes ANXA5 as a prime example of a translatable biomarker discovered through multi\u2010omics integration. It functions dually as a prognostic indicator and a predictive biomarker for immunotherapy, offering a tangible framework for patient stratification and personalized therapeutic strategies in glioma, thereby bridging a critical gap toward clinical translation.<\/jats:p>","DOI":"10.1002\/biof.70092","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T03:45:13Z","timestamp":1773805513000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>ANXA5<\/scp>\n                    : A Multi\u2010Omics\u2010Derived,\n                    <scp>UPR<\/scp>\n                    \u2010Associated Dual\u2010Function Biomarker for Prognosis and Immunotherapy Response Prediction in Glioma"],"prefix":"10.1002","volume":"52","author":[{"given":"Jiachong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Haikou Affiliated Hospital of Central South University Xiangya 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