Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses

Lay abstract Using viruses in the treatment of cancer goes back to the early 20th century. One of the promising fields in cancer virotherapy is viruses' ability to preferentially lysis tumor cells, either naturally or genetically engineered cells; these viruses are termed 'oncolytic viruses.' As with other therapeutic strategies, resistance to the oncolytic viruses is the main challenge in their application in clinical trials. This review summarizes the mechanisms of resistance to oncolytic viruses and the strategies that have been used to overcome these challenges. Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.