Efficacy and safety of oncolytic herpes simplex virus therapy in solid tumors: a systematic review and meta-analysis of 38 clinical trials

Abstract Background Oncolytic herpes simplex virus (oHSV) therapy represents a novel immunotherapeutic approach for solid tumors. Despite regulatory approval of talimogene laherparepvec (T-VEC) for advanced melanoma, comprehensive pooled estimates of efficacy and safety across diverse solid tumor types and multiple oHSV agents remain unavailable. We conducted a systematic review and meta-analysis to evaluate the clinical outcomes of oHSV therapy in adult patients with solid tumors. Methods We systematically searched PubMed, Cochrane Library, Scopus, Web of Science, ScienceDirect, and Embase from inception to September 19, 2025. We included phase I-III clinical trials and prospective interventional studies evaluating any replication-competent oHSV agent in adults (≥ 18 years) with solid tumors. Primary outcomes were objective response rate (ORR), disease control rate (DCR), 12- and 24-month overall survival (OS), and safety (any treatment-related adverse event [TRAE], grade 3–5 TRAEs). Pooled proportions with 95% confidence intervals (CIs) were calculated using a DerSimonian-Laird random-effects model with Freeman-Tukey double arcsine transformation. Hartung-Knapp adjustment was applied to primary outcomes, and prediction intervals were reported for ORR, DCR, and OS. Heterogeneity was assessed using the I² statistic. Subgroup analyses were pre-specified by cancer type and virus type. Publication bias was evaluated using Egger’s test, trim-and-fill analysis, and contour-enhanced funnel plots. Findings Thirty-eight studies comprising 2,982 patients were included. The pooled ORR across 33 studies ( n = 1,409) was 29.6% (95% CI: 23.5%–36.6%; I²=74.6%). The pooled DCR across 21 studies ( n = 699) was 55.8% (95% CI: 42.8%–68.1%; I²=81.1%). Skin cancers demonstrated the highest response rates (ORR: 55.6%, 95% CI: 33.7%–75.4%; single study). The pooled 12-month and 24-month OS rates were 69.6% (95% CI: 60.7%–77.3%; I²=78.0%) and 52.6% (95% CI: 44.5%–60.6%; I²=72.2%), respectively. Any TRAE occurred in 86.3% (95% CI: 70.8%–94.2%; I²=92.7%), with grade 3–5 TRAEs in 20.5% (95% CI: 13.6%–29.6%). Treatment-related mortality was low at 2.5% (95% CI: 1.6%–4.0%; I²=0%). Pyrexia (46.9%; 38 studies, 1,304 patients) and chills (34.0%) were the most common TRAEs. Sensitivity analyses confirmed robustness, but publication bias was detected for DCR and any TRAEs. Interpretation oHSV therapy demonstrates modest anti-tumor activity with notable heterogeneity across tumor types. The safety profile is manageable, with low rates of treatment discontinuation and treatment-related mortality. The strongest evidence supports the use of T-VEC in injectable melanoma and skin cancers. Findings in breast, colorectal, pancreatic, and other non-melanoma tumors should be considered hypothesis-generating and require confirmation in larger, cancer-type-specific trials. The high heterogeneity underscores the need for optimized viral backbones and biomarker-driven patient selection. These findings support continued clinical development of oHSV as a versatile immunotherapy platform. Trial registration This systematic review and meta-analysis was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420261279371. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines.