Optimizing Oncolytic Virotherapy for Malignant Glioma: From Bench to Bedside

Malignant glioma is a highly aggressive brain tumor characterized by frequent recurrence, poor prognosis, and limited responsiveness to standard therapies. Glioblastoma multiforme, the most common and aggressive subtype, further complicates treatment due to its infiltrative nature, genetic heterogeneity, the protective blood-brain barrier, and an immunosuppressive microenvironment. Despite aggressive treatment strategies such as surgical resection combined with chemoradiotherapy, the median survival for malignant glioma patients remains low, highlighting the urgent need for more effective therapeutic approaches. Oncolytic virotherapy (OVT), a dual-modality approach that combines immunotherapy and biotherapy, has emerged as a promising alternative. Oncolytic viruses (OVs) can replicate continuously, disseminate within the tumor, and stimulate anti-tumor immunity, offering distinct advantages in targeting invasive and immunologically "cold" malignant glioma. However, the efficacy of OVT in clinical trials remains unsatisfactory, particularly in single-agent regimens. This limitation is primarily attributed to the viruses' limited replication efficiency, suboptimal immune induction, premature clearance by antiviral immune responses, and the blood-brain barrier, which impedes effective intracranial delivery. Thus, further optimization of viral modifications, delivery systems, and treatment regimens is critical to enhancing therapeutic potency before OVT can become a standard therapy for malignant glioma. This review systematically summarizes current strategies for enhancing OVs, including genetic engineering, chemical functionalization, and carrier-based delivery. Furthermore, it highlights combination therapies that aim to synergistically enhance therapeutic efficacy through chemotherapy, radiotherapy, and immunotherapy. Finally, the review emphasizes recent clinical trials leveraging these enhancement strategies, aiming to offer novel insights for translating OVs from research to clinical practice.