Flaviviruses in AntiTumor Therapy

Abstract

Oncolytic viruses offer a promising approach to tumor treatment. These viruses not only have a direct lytic effect on tumor cells but can also modify the tumor microenvironment and activate antitumor immunity. Due to their high pathogenicity, flaviviruses have often been overlooked as potential antitumor agents. However, with recent advancements in genetic engineering techniques, an extensive history with vaccine strains, and the development of new attenuated vaccine strains, there has been a renewed interest in the Flavivirus genus. Flaviviruses can be genetically modified to express transgenes at acceptable levels, and the stability of such constructs has been greatly improving over the years. The key advantages of flaviviruses include their reproduction cycle occurring entirely within the cytoplasm (avoiding genome integration) and their ability to cross the blood-brain barrier, facilitating the systemic delivery of oncolytics against brain tumors. So far, the direct lytic effects and immunomodulatory activities of many flaviviruses have been widely studied in experimental animal models across various types of tumors. In this review, we delve into the findings of these studies and contemplate the promising potential of flaviviruses in oncolytic therapies.

Keywords: antitumor therapy; cancer immunotherapy; flavivirus; immunotherapy; oncolytic viruses; recombinant strain; viral vector.

Figure 1

Panel (A)—Life cycle of flaviviruses. (1)—Attachment to cell surface using glycosaminoglycans (GAG), (2)—virus entry into the host cell via receptor-mediated endocytosis, (3,4)—release of the genomic RNA into the cytoplasm through membrane fusion mediated by viral glycoproteins, (5)—translation and polyprotein processing, (6)—immature particles pass through the Golgi, (7)—intracellular budding, (8)—virus maturation, and (9)—virus release. Panel (B)—The flavivirus genome is represented by capped ∼11 kb positive strand ssRNA with a single open reading frame. The genomic RNA is translated as a single polyprotein subsequently cleaved into three structural proteins (C—capsid, prM/M—precursor membrane, and E—envelope) and seven nonstructural (NS) proteins responsible for coordinating viral replication, assembly, and modulation of host defense mechanisms [28,32].