A Decade of Oncolytic Virotherapy in Pediatric Cancers: A Systematic Review of Safety, Immune Awakening, and Emerging Efficacy.
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Oncolytic virotherapy employs genetically modified viruses to selectively lyse tumor cells while activating antitumor immune responses. In pediatric oncology, where outcomes for high-grade gliomas and refractory solid tumors remain poor, oncolytic viruses represent a promising therapeutic strategy. A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, including searches of PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov for studies published between 2015 and 2025 that evaluated oncolytic virotherapy in patients aged 18 years or younger. Data on safety, efficacy, and immune-related outcomes were extracted, study quality was assessed using the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool, and the certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Ten early-phase clinical trials involving 115 pediatric patients met the inclusion criteria. Investigated viral platforms included herpes simplex virus type 1 (G207, HSV1716), adenovirus (DNX-2401, ICOVIR-5, Ad-TD-nsIL12), T-VEC (HSV-1), poliovirus (PVSRIPO), Seneca Valley virus, and reovirus. Across studies, no treatment-related deaths or persistent grade 3 or higher toxicities were reported, and adverse events were generally mild and transient. Radiologic or clinical disease control rates ranged from 20% to 90%, with median overall survival between 11 and 18 months in selected central nervous system tumor cohorts. Translational analyses demonstrated increased CD8⁺ T-cell infiltration, upregulation of interferon-γ and interleukin-6 signaling pathways, and evidence of transient viral replication, supporting immune-mediated antitumor mechanisms. Overall risk of bias was moderate, while the certainty of evidence was rated as low for safety outcomes and very low for efficacy. These findings indicate that oncolytic virotherapy is safe, feasible, and biologically active in children with malignant brain and solid tumors, and that preliminary survival signals and consistent immune activation support further investigation through larger, multicenter randomized trials and combination strategies with radiotherapy or immune checkpoint inhibitors.