溶瘤病毒靶向治疗肿瘤的策略

近年来，随着国内外几款溶瘤病毒制剂的相继上市，溶瘤病毒疗法成为肿瘤免疫治疗的焦点。溶瘤病毒可选择性感染并裂解肿瘤细胞，同时释放肿瘤相关抗原激活机体的抗肿瘤免疫反应，达到杀伤肿瘤细胞和抑制肿瘤生长的目的。溶瘤病毒对肿瘤的靶向杀伤作用决定了其安全性和溶瘤效果。为了开发出安全高效的溶瘤病毒，目前主要采用以下策略：利用某些病毒载体对肿瘤细胞的天然靶向性，使溶瘤病毒选择性地在肿瘤细胞内复制并杀伤肿瘤细胞；或者对病毒基因组进行缺失和插入等修饰，通过靶向肿瘤细胞特异性表面受体、胞内信号通路或者肿瘤微环境等提高溶瘤病毒的肿瘤靶向性。其中，肿瘤微环境中的低氧状态、新血管生成以及免疫抑制状态等都可成为溶瘤病毒的靶点。而溶瘤病毒通过表达细胞因子和免疫检查点抑制剂，或者与CAR-T细胞联合作用，靶向调节肿瘤微环境中免疫抑制状态，成为提高溶瘤病毒肿瘤靶向性的常用方法。本文将对以上溶瘤病毒靶向治疗肿瘤策略的研究进展进行综述。

Strategies for Tumor Targeting Therapy by Oncolytic Viruses

In recent years, several oncolytic virus preparations has been approved for marketing, leading to the oncolytic virus therapy to become the focus of tumor immunotherapy. Oncolytic viruses can selectively infect and lyse tumor cells, and release tumor-associated antigens (TAAs) to activate anti-tumor immune response to inhibit tumor growth. The safety and efficacy of oncolytic virus are determined by its targeted killing effect on tumor. In order to develop safe and efficient oncolytic viruses, the following strategies are mainly adopted: taking advantage of the natural target of some virus on tumor cells to make oncolytic viruses selectively replicate in tumor cells and kill tumor cells; alternatively, the viral genome can be modified by deletion of some virus gene or insertion of some exogenous gene to promote virus targeting tumor cell-specific surface receptors, intracellular signaling pathways, or the tumor microenvironment to improve the targeting ability of oncolytic viruses. In tumor microenvironment, hypoxia, neovascularization and immunosuppression usually can be targets of oncolytic viruses. In order to regulate immunosuppressive state, oncolytic viruses are commonly used to express cytokines and immune checkpoint inhibitors, or combine with CAR-T cells. In this paper, we will review the research progress of therapy strategies of the oncolytic virus-targeted tumor.