Oncolytic Herpes Simplex Virus for Glioblastoma: Molecular Engineering, Tumor Microenvironment Barriers, and Clinical Translation.

Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, with limited survival benefit from the current standard of care consisting of maximal safe resection, radiotherapy, and temozolomide-based chemotherapy. The highly infiltrative growth pattern, profound intratumoral heterogeneity, and strongly immunosuppressive tumor microenvironment together contribute to therapeutic resistance and frequent recurrence. In this context, oncolytic herpes simplex virus (oHSV) has emerged as a promising therapeutic platform for glioblastoma because of its dual capacity to directly lyse tumor cells and stimulate antitumor immune responses. In addition, the large viral genome and well-characterized biology of herpes simplex virus enable extensive genetic engineering to improve tumor selectivity, safety, and immunomodulatory function. In this review, we summarize the molecular design strategies that have driven the development of oHSV for glioblastoma, including attenuation of neurovirulence, enhancement of tumor-selective replication, and arming with immune-stimulatory transgenes. We further discuss the major biological barriers within the GBM tumor microenvironment that continue to limit therapeutic efficacy, with particular attention given to representative engineered oHSV platforms and the lessons learned from preclinical and early-phase clinical studies. A dedicated section examines these barriers in detail, including restricted intratumoral viral spread, antiviral innate immunity, and immunosuppressive myeloid cell dominance. We also review current efforts to improve outcomes through rational combination strategies with radiotherapy, immune checkpoint blockade, cytokine modulation, and other multimodal approaches. Although encouraging advances have been achieved, the clinical translation of oHSV therapy for glioblastoma still faces substantial challenges in patient selection, delivery optimization, response assessment, and treatment integration. A deeper understanding of virus-host-tumor interactions and more precise engineering of viral platforms may help unlock the full potential of oHSV-based therapy. Overall, oHSV represents one of the most compelling translational approaches in glioblastoma and provides a valuable framework for the development of mechanism-driven viro-immunotherapy in neuro-oncology.