Abdelmageed Alaa A, Dewhurst Stephen, Ferran Maureen C
Biomedical Genetics and Genomics Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Viruses. 2024 Dec 25;17(1):16. doi: 10.3390/v17010016.
Vesicular Stomatitis Virus (VSV) has emerged as a promising candidate for various clinical applications, including vaccine development, virus pseudotyping, and gene delivery. Its broad host range, ease of propagation, and lack of pre-existing immunity in humans make it ideal for therapeutic use. VSV's potential as an oncolytic virus has garnered attention; however, resistance to VSV-mediated oncolysis has been observed in some cell lines and tumor types, limiting its effectiveness. This review provides a detailed analysis of recent advances in VSV-based oncolysis, focusing on resistance mechanisms such as sustained type-I IFN signaling, upregulation of ISGs, immune cell activation, the tumor microenvironment (TME), and tumor-intrinsic factors. Strategies to overcome resistance include enhancing viral oncoselectivity, inhibiting IFN responses, modulating the TME, and combining VSV with chemotherapies, radiation, and immune checkpoint inhibitors. Several VSV-based phase I/II clinical trials show promise; however, addressing resistance and developing novel strategies to enhance therapeutic efficacy are essential for realizing the full potential of VSV oncolytic virotherapy. Future research should focus on patient-specific approaches, as tumor heterogeneity implies varying resistance mechanisms. Personalized treatments tailored to tumor molecular profiles, along with identifying biomarkers predictive of resistance to VSV oncolysis, will enhance patient selection and enable more effective, individualized VSV-based therapies.
水泡性口炎病毒（VSV）已成为各种临床应用中颇具前景的候选者，包括疫苗开发、病毒假型化和基因递送。其广泛的宿主范围、易于传播以及人类中不存在预先存在的免疫力使其成为治疗用途的理想选择。VSV作为溶瘤病毒的潜力已受到关注；然而，在一些细胞系和肿瘤类型中已观察到对VSV介导的溶瘤作用的抗性，这限制了其有效性。本综述详细分析了基于VSV的溶瘤作用的最新进展，重点关注抗性机制，如持续的I型干扰素信号传导、干扰素刺激基因（ISG）的上调、免疫细胞激活、肿瘤微环境（TME）和肿瘤内在因素。克服抗性的策略包括增强病毒的肿瘤选择性、抑制干扰素反应、调节肿瘤微环境以及将VSV与化疗、放疗和免疫检查点抑制剂联合使用。几项基于VSV的I/II期临床试验显示出前景；然而，解决抗性问题并开发新的策略以提高治疗效果对于实现VSV溶瘤病毒疗法的全部潜力至关重要。未来的研究应侧重于针对患者的方法，因为肿瘤异质性意味着抗性机制各不相同。根据肿瘤分子谱定制个性化治疗，以及识别预测对VSV溶瘤作用抗性的生物标志物，将改善患者选择并实现更有效、个性化的基于VSV的治疗。
