Targeting leucine-rich repeat kinase 2 overcomes resistance to oncolytic herpes simplex virus-based therapies in glioblastoma.

Glioblastoma (GBM) is an incurable brain tumor characterized by high heterogeneity. Oncolytic viruses (OVs) are an approved therapy, but their efficacy is often limited by poor cellular permissiveness to infection. Here we screen bioactive compounds to identify enhancers of oncolytic herpes simplex virus (oHSV) in GBM and discover a brain-penetrant leucine-rich repeat kinase 2 (LRRK2) inhibitor as the strongest sensitizer. Pharmacological LRRK2 inhibition potentiates oHSV infection and oncolysis across diverse GBM cell lines and improves therapeutic outcomes in patient-derived xenograft and orthotopic models. Mechanistically, LRRK2 interacts with and promotes STAT1 phosphorylation at Y701, which drives interferon-independent antiviral responses. Consequently, LRRK2 inhibition attenuates these host defenses, thereby enhancing tumor-selective viral replication. Elevated LRRK2 levels in GBM correlate with reduced oHSV sensitivity, suggesting LRRK2 as a predictive biomarker for tumors amenable to oHSV therapy. Our findings support the combination of LRRK2 inhibitors with oHSV as a promising therapeutic strategy for aggressive GBM.