靶向宿主代谢重编程的溶瘤病毒调控策略

溶瘤病毒是一类天然的或经过基因编辑后能特异性在肿瘤细胞中复制、发挥抗肿瘤效应的病毒。溶瘤病毒的抗肿瘤效应主要通过以下两个方面实现：a. 直接的溶瘤效应,例如诱导肿瘤细胞发生凋亡、促使细胞裂解等;b. 溶瘤病毒作为一种激活免疫的药物,通过诱导机体产生强烈的抗肿瘤免疫,达到清除肿瘤的目的。溶瘤病毒疗法作为免疫疗法的一个重要分支,因其具有肿瘤特异性,便于基因改造等优点,成为该领域的研究热点。截至目前,处在临床实验招募和完成阶段的溶瘤病毒疗法虽然已达100多例,但已批准上市的产品仅有4款。溶瘤疗法应用于肿瘤治疗领域还面临着诸多挑战。因此,系统性回顾溶瘤病毒的改造策略,深入了解溶瘤病毒的生物学过程显得尤为必要。病毒依赖于宿主完成复制、增殖过程,其生物学过程与宿主的代谢状态密切相关。肿瘤的标志性特征为代谢重编程,即肿瘤细胞重新构建代谢网络以满足指数生长和增殖的需求并防止氧化应激的过程。通常包括糖酵解的增强和谷氨酰胺分解,以及线粒体功能和氧化还原稳态的变化。通过靶向宿主代谢重编程增强溶瘤病毒的复制、溶瘤能力是当前极具前景的方向。本文综述溶瘤病毒的临床应用现状及与代谢相关的调控机制,为进一步开发新型溶瘤病毒以及联用方式提供新的思路。

The Regulation Strategy of Oncolytic Viruses by Targeting Host Metabolic Reprogramming

Oncolytic viruses are a class of viruses that are naturally or genetically engineered to replicate specifically in tumor cells and exert anti-tumor effects. The anti-tumor effect of oncolytic virus is mainly achieved through the following two aspects: (1) direct oncolytic effect, such as inducing apoptosis of tumor cells and promoting cell lysis; (2) as a drug that activates immunity, oncolytic viruses induce the body to produce strong anti-tumor immunity and achieve the purpose of clearing tumors. As an important branch of immunotherapy, oncolytic viral therapy has become a research hotspot in this field due to its tumor specificity and convenient genetic modification. Until now, only four products have been approved for marketing, despite more than 100 cases of oncolytic viral therapies in the recruitment and completion stages of clinical trials. There continue to be many challenges in the application of oncolytic therapy in oncology treatment. Therefore, a systematic review of oncolytic virus modification strategies and an in-depth understanding of the biological processes of oncolytic viruses are all the more necessary. Viruses are host-dependent in their replication and proliferation processes, and their biological processes are closely related to the metabolic state of the host. The hallmark feature of tumors is metabolic reprogramming, the process by which tumor cells reconsider their metabolic networks to meet the demands of exponential growth and proliferation and to prevent oxidative stress. This typically includes enhanced glycolysis and glutaminolysis, as well as changes in mitochondrial function and redox homeostasis.The replication of oncolytic viruses requires the synthesis of biological macromolecules, such as amino acids, lipids, nucleotides, etc. Viruses themselves do not encode relevant enzymes, so they often need to use the metabolic pathways of their host cells to synthesize the substances they need. Enhancing the replication and oncolytic ability of oncolytic viruses by targeting host metabolic reprogramming is a promising direction. It has been shown that lipid metabolism and intermediates are one of the ways in which viruses engage in dialogue with their hosts, and lipid rafts are essential components for oncolytic viruses to perform their infection and replication functions. Cholesterol depletion in host cells has shown conflicting results, presumably related to the type of virus. For example, the dependence of envelope and non-envelope viruses on lipid synthesis may differ, although this needs more literature support. The idea that enhanced glycolytic levels in host cells promote the infection, replication, and anti-tumor effects of oncolytic viruses is equally controversial. Oncolytic viruses replicate to a degree comparable to that of proliferative tumor cells, and both rely on glutamine metabolism to participate in the synthesis of biological macromolecules. Adenoviruses and VSV are significantly less able to replicate in states where the glutamine metabolic pathway is suppressed. Similarly, the level of host nucleotide metabolism is closely related to the replication capacity of oncolytic viruses, and enhancing RNA reductase (RR) activity can promote HSV replication in tumors. Therefore, the use of oncolytic viruses to regulate host metabolic reprogramming, or in combination with drugs that can regulate host metabolism, is one of the directions to further improve oncolytic virus anti-tumor efficacy.