Gene Therapy in Glioblastoma: From Vector Engineering to Immune Microenvironment Reprogramming

Abstract

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, characterized by extensive intratumoral heterogeneity, diffuse infiltration, profound immunosuppression, and an invariably poor prognosis despite multimodal treatment strategies. Although maximal safe surgical resection followed by radiotherapy and temozolomide constitutes the current standard of care, therapeutic resistance and tumor recurrence remain nearly universal, underscoring the urgent need for innovative treatment modalities. In this context, gene therapy has emerged as a promising therapeutic paradigm capable of addressing several biological limitations associated with conventional therapies through targeted genetic modulation and immune microenvironment reprogramming. This narrative review comprehensively summarizes the advances achieved between 2016 and 2026 in GBM-directed gene therapy. Particular emphasis is placed on the engineering principles, biological characteristics, and translational applications of viral vectors including retroviral, adenoviral, and adeno-associated viral systems as well as emerging non-viral delivery platforms such as lipid nanoparticles, polymeric nanocarriers, electroporation, engineered exosomes, messenger RNA technologies, and CRISPR/Cas-based genome editing. Furthermore, the review discusses recent developments in oncolytic virotherapy, suicide gene systems, RNA interference strategies, immune-stimulatory gene delivery, and adoptive cellular gene therapies. Beyond vector technology, this review highlights the critical role of immune microenvironment remodeling in improving therapeutic efficacy. Current evidence suggests that successful gene therapy should not solely focus on tumor cell eradication but should also promote durable antitumor immunity through enhanced antigen presentation, increased lymphocyte infiltration, reversal of myeloid-mediated immunosuppression, and rational integration with immune checkpoint blockade, dendritic cell vaccines, CAR-T cell therapy, and other multimodal immunotherapeutic approaches. Finally, ongoing clinical trials, translational challenges, manufacturing considerations, biomarker-guided patient selection, and future perspectives are critically discussed to provide a comprehensive overview of the evolving landscape of gene therapy for glioblastoma.