Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
School of Life Sciences, Westlake University, Hangzhou, 310024, China.
J Hematol Oncol. 2024 May 23;17(1):36. doi: 10.1186/s13045-024-01554-5.
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.
溶瘤病毒 (OVs) 为治疗实体瘤提供了一种新方法；然而，由于各种限制因素，其疗效常常不尽如人意。为了解决这一挑战，我们设计了一种含有神经元特异性 microRNA-124 和粒细胞-巨噬细胞集落刺激因子 (GM-CSF) 靶点的 OV，显著提高了其神经元安全性，同时最小化了其复制能力。此外，我们使用全基因组 CRISPR 筛选鉴定了 PARP1 作为 HSV-1 复制限制因子。在胶质母细胞瘤 (GBM) 和三阴性乳腺癌 (TNBC) 模型中，我们表明 OV 和 PARP 抑制剂 (PARPi) 的联合治疗与单一疗法相比具有更好的疗效。此外，单细胞 RNA 测序 (scRNA-seq) 显示，这种联合治疗使 TNBC 对免疫检查点阻断更敏感，并且包含免疫检查点抑制剂 (ICI) 进一步提高了荷瘤小鼠的存活率。PARPi 和 ICI 的联合使用协同增强了 OV 建立持久的肿瘤特异性免疫反应的能力。我们的研究有效地克服了 OV 治疗的固有局限性，为 TNBC、GBM 和其他恶性肿瘤的临床治疗提供了有价值的见解。
