Long non-coding RNAs in glioblastoma: from molecular drivers to therapeutic targets

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor in adults and remains associated with poor clinical outcomes despite advances in surgical resection, radiotherapy, and temozolomide-based chemotherapy. Its remarkable molecular heterogeneity, highly immunosuppressive tumor microenvironment, and intrinsic therapeutic resistance continue to limit the effectiveness of current treatment strategies. Long non-coding RNAs (lncRNAs), transcripts exceeding 200 nucleotides in length that lack protein-coding capacity, have emerged as critical regulators of GBM biology through transcriptional, post-transcriptional, and epigenetic mechanisms. Acting as competing endogenous RNAs, chromatin modifiers, molecular scaffolds, and regulators of RNA-binding proteins, lncRNAs orchestrate key oncogenic pathways controlling proliferation, invasion, angiogenesis, stemness, metabolic reprogramming, immune evasion, and resistance to chemotherapy and radiotherapy. This review provides a comprehensive overview of lncRNA biogenesis, classification, and mechanisms of action, followed by an updated synthesis of oncogenic and tumor-suppressive lncRNAs implicated in GBM progression. Particular emphasis is placed on emerging evidence demonstrating how immunophenotype-related lncRNAs regulate immune cell infiltration, immune checkpoint signaling, and the immunosuppressive glioblastoma microenvironment, highlighting their potential to improve patient stratification and guide immunotherapeutic approaches. We also discuss the growing clinical utility of lncRNAs as diagnostic, prognostic, and predictive biomarkers, including circulating lncRNAs and lncRNA-based molecular signatures. Finally, we examine current and emerging therapeutic strategies targeting lncRNAs, including nanoparticle-mediated delivery systems designed to overcome the blood-brain barrier. Advances in single-cell and spatial transcriptomic technologies are further expanding our understanding of lncRNA-mediated regulatory networks and intratumoral heterogeneity, supporting the development of precision medicine strategies. Collectively, lncRNAs represent promising biomarkers and therapeutic targets with significant potential to improve the diagnosis, prognosis, and treatment of glioblastoma.