A novel oncolytic herpes simplex virus (oHSV) expressing interleukin-2 (IL-2), G47Δ-mIL2, was developed and tested in mouse models of glioblastoma (GBM). The virus was engineered using the flip-flop HSV-BAC system to deliver IL-2 locally within the tumor microenvironment (TME). G47Δ-mIL2 showed significant antitumor activity in orthotopic GBM models, extending median survival by 63% in the 005 GSC model and 35% in the CT-2A model, without systemic toxicity. The therapeutic effect was associated with increased infiltration of CD8⁺ T cells and CD4⁺ T cells into the TME, with CD4⁺ T cells playing a critical role. IL-2 expression by G47Δ-mIL2 was localized within the TME, avoiding systemic toxicity. Neutralization of IL-2 abrogated the antitumor efficacy of G47Δ-mIL2, confirming the importance of local IL-2 expression. Anti-PD-1 immune checkpoint blockade did not significantly improve the therapeutic outcome. These findings suggest that G47Δ-mIL2 is a promising candidate for GBM treatment, targeting GBM stem-like cells (GSCs) and inducing antitumor immunity. The study highlights the potential of IL-2-expressing oHSV as a novel therapeutic approach for GBM.A novel oncolytic herpes simplex virus (oHSV) expressing interleukin-2 (IL-2), G47Δ-mIL2, was developed and tested in mouse models of glioblastoma (GBM). The virus was engineered using the flip-flop HSV-BAC system to deliver IL-2 locally within the tumor microenvironment (TME). G47Δ-mIL2 showed significant antitumor activity in orthotopic GBM models, extending median survival by 63% in the 005 GSC model and 35% in the CT-2A model, without systemic toxicity. The therapeutic effect was associated with increased infiltration of CD8⁺ T cells and CD4⁺ T cells into the TME, with CD4⁺ T cells playing a critical role. IL-2 expression by G47Δ-mIL2 was localized within the TME, avoiding systemic toxicity. Neutralization of IL-2 abrogated the antitumor efficacy of G47Δ-mIL2, confirming the importance of local IL-2 expression. Anti-PD-1 immune checkpoint blockade did not significantly improve the therapeutic outcome. These findings suggest that G47Δ-mIL2 is a promising candidate for GBM treatment, targeting GBM stem-like cells (GSCs) and inducing antitumor immunity. The study highlights the potential of IL-2-expressing oHSV as a novel therapeutic approach for GBM.