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Updated: Jun 25, 2025
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening
Yiye Zhong1, Huangying Le1, Xue Zhang1
1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Abstract:
Oncolytic viruses (OVs) offer a novel approach to treat solid tumors; however, their efficacy is frequently suboptimal due to various limiting factors. To address this challenge, we engineered an OV containing targets for neuron-specific microRNA-124 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), significantly enhancing its neuronal safety while minimally compromising its replication capacity. Moreover, we identified PARP1 as an HSV-1 replication restriction factor using genome-wide CRISPR screening. In models of glioblastoma (GBM) and triple-negative breast cancer (TNBC), we showed that the combination of OV and a PARP inhibitor (PARPi) exhibited superior efficacy compared to either monotherapy. Additionally, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy sensitized TNBC to immune checkpoint blockade, and the incorporation of an immune checkpoint inhibitor (ICI) further increased the survival rate of tumor-bearing mice. The combination of PARPi and ICI synergistically enhanced the ability of OV to establish durable tumor-specific immune responses. Our study effectively overcomes the inherent limitations of OV therapy, providing valuable insights for the clinical treatment of TNBC, GBM, and other malignancies.
Insights
Engineered oncolytic viruses (OVs) show enhanced safety and efficacy against glioblastoma and triple-negative breast cancer. Combining OVs with PARP inhibitors and immune checkpoint inhibitors improves tumor-specific immune responses and survival rates.
Area of Science:
- Oncolytic virotherapy
- Cancer immunotherapy
- Molecular oncology
Background:
- Oncolytic viruses (OVs) are promising cancer therapeutics but face limitations in efficacy and safety.
- Engineering OVs with neuron-specific microRNA-124 and GM-CSF enhances neuronal safety without significantly impairing viral replication.
- PARP1 was identified as an HSV-1 restriction factor using genome-wide CRISPR screening.
Discussion:
- Combination therapy of engineered OV with a PARP inhibitor (PARPi) demonstrated superior efficacy in glioblastoma (GBM) and triple-negative breast cancer (TNBC) models compared to monotherapy.
- Single-cell RNA sequencing revealed that OV + PARPi sensitized TNBC to immune checkpoint blockade (ICB).
- Incorporating an immune checkpoint inhibitor (ICI) further improved survival in tumor-bearing mice.
Key Insights:
- Engineered OV exhibits improved safety and efficacy profiles.
- PARP1 is a key factor in restricting HSV-1 replication.
- Combination strategies involving OVs, PARPi, and ICIs synergistically enhance anti-tumor immunity.
Outlook:
- This study provides a robust framework for overcoming OV limitations in clinical settings.
- The findings offer valuable insights for developing novel combination therapies for TNBC, GBM, and other solid tumors.
- Further research into synergistic combinations could lead to improved patient outcomes in oncology.
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