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

  • Nat Commun. 2026 Feb 28;17(1):3324. doi: 10.1038/s41467-026-70132-9.
Yaning Qin  #  1  2 ,  Zhiqi Liang  #  1  2 ,  Mengqin Yu  #  1  3 ,  Nanqian Lin  #  1  2 ,  Naizhen Wang  #  1  2 ,  Xuanke Huang  #  4 ,  Shi Chen  #  1  2 ,  Qun Peng  1  2 ,  Yanhua Lin  1  2 ,  Heqin Wang  1  2 ,  Yipeng Rao  1  2 ,  Zilong Xu  1  2 ,  Shenghua Huang  1  2 ,  Jingjing Cai  1  2 ,  Yukui Li  5 ,  Jun Zhang  1  2 ,  Chaolong Lin  6  7 ,  Guowei Tan  8  9 ,  Ningshao Xia  10  11 ,  Chenghao Huang  12  13
Affiliations
  • 1. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China.
  • 2. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 3. Department of Clinical Laboratory, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China.
  • 4. School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 5. Department of Neurosurgery, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
  • 6. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 7. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 8. School of Medicine, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 9. Department of Neurosurgery, First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. [email protected].
  • 10. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 11. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 12. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, Xiamen University, Xiamen, Fujian, China. [email protected].
  • 13. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 41764166 DOI: 10.1038/s41467-026-70132-9
Abstract

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.

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