MicroRNA-138 regulation promotes the efficacy of oncolytic herpes virus G47Δ for malignant brain tumor therapy

G47Δ, a third-generation oncolytic herpes simplex virus type 1, is a promising therapeutic agent for malignant glioma. We investigated whether inhibition of host microRNA-138 (miR-138), a regulator of the viral immediate-early protein ICP0, could enhance its efficacy. <i>In vitro</i>, miR-138 suppression increased viral protein expression, progeny virus production, and cytotoxicity in human glioblastoma and murine Neuro2a cells, whereas overexpression suppressed these effects. Neuro2a cells stably silenced for miR-138 showed tumor regression in 9 of 13 syngeneic mice, but not in athymic mice or following CD8⁺ T cell depletion, indicating dependence on adaptive immunity. Mechanistically, miR-138 directly targeted signal transducer and activator of transcription 1 (STAT1) mRNA: Its inhibition increased STAT1 and enhanced MHC class I expression. In bilateral subcutaneous tumors, miR-138 inhibition suppressed growth on the treated side, but contralateral tumor suppression required combination with G47Δ, suggesting systemic antitumor immunity involvement. <i>In vivo</i> electroporation-mediated miR-138 inhibition in subcutaneous tumors elevated STAT1 and suppressed growth. G47Δ combined with <i>in vivo</i> miR-138 inhibition significantly augmented efficacy compared with G47Δ alone. These findings identify miR-138 as both an antiviral regulator and immune modulator, and demonstrate that its inhibition potentiates G47Δ efficacy, providing rationale for a novel therapeutic strategy for malignant brain tumors.