Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening

Author:

Zhong Yiye,Le Huangying,Zhang Xue,Dai Yao,Guo Fang,Ran Xiaojuan,Hu Guohong,Xie Qi,Wang Dawei,Cai Yujia

Abstract

AbstractOncolytic 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.

Funder

National Natural Science Foundation of China

Yangfan project from the Science and Technology Commission of Shanghai Municipality

Start-up Fund by Shanghai Jiao Tong University

Guangci Distinguished Young Scholars Training Program

Key-research Fund from State Key Laboratory of Medical Genomics

Fundamental Research Funds for the Central Universities

National Key Research and Development Program of China

Science and Technology Innovation Action Plan of Shanghai

Key Forward-Looking Fund from Shanghai Jiao Tong University

Publisher

Springer Science and Business Media LLC

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