Glioblastoma (GBM) is a highly immunosuppressive and often fatal primary brain tumor with limited treatment options. The study introduces a novel oncolytic herpes simplex virus (oHSV) expressing interleukin 2 (IL-2) (G47Δ-mIL2) to locally deliver IL-2 within the tumor microenvironment (TME). G47Δ-mIL2 was engineered using the flip-flop HSV BAC system and tested in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261). In the 005 and CT-2A models, G47Δ-mIL2 significantly prolonged median survival without systemic IL-2-related toxicity. The therapeutic activity was associated with increased intratumoral infiltration of CD8+ T cells, which was critically dependent on the release of IL-2 within the TME. Depletion of CD4+ T cells abrogated the therapeutic efficacy, highlighting their critical role. Anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2. These findings suggest that G47Δ-mIL2 is effective in stimulating antitumor immunity against orthotopic GBM and may target GBM stem-like cells (GSCs). Further clinical investigation is warranted.Glioblastoma (GBM) is a highly immunosuppressive and often fatal primary brain tumor with limited treatment options. The study introduces a novel oncolytic herpes simplex virus (oHSV) expressing interleukin 2 (IL-2) (G47Δ-mIL2) to locally deliver IL-2 within the tumor microenvironment (TME). G47Δ-mIL2 was engineered using the flip-flop HSV BAC system and tested in orthotopic mouse GBM models (005 GSC, CT-2A, and GL261). In the 005 and CT-2A models, G47Δ-mIL2 significantly prolonged median survival without systemic IL-2-related toxicity. The therapeutic activity was associated with increased intratumoral infiltration of CD8+ T cells, which was critically dependent on the release of IL-2 within the TME. Depletion of CD4+ T cells abrogated the therapeutic efficacy, highlighting their critical role. Anti-PD-1 immune checkpoint blockade did not improve the therapeutic outcome of G47Δ-mIL2. These findings suggest that G47Δ-mIL2 is effective in stimulating antitumor immunity against orthotopic GBM and may target GBM stem-like cells (GSCs). Further clinical investigation is warranted.