Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy

Abstract

Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.

Keywords: immune virotherapy; nanomedicine; oncolytic virotherapy; viral biotechnology; virus engineering.

Figure 1

Mechanisms of action of oncolytic viruses. The replication of virus inside the tumor cell triggers immunogenic cell death (ICD), followed by release of tumor antigens that activate the immune system, remodeling of TME, activation of the antiangiogenic mechanisms, increase in viral replication in tumor-mutated cells, and spread of the viral infection to other tumor cells [9,55,56,57,58] (BioRender.com).

Figure 2

Oncolytic viruses (OVs) enter the tumor cell through endocytosis or by targeting one or multiple receptors. The mechanisms of direct oncolysis by OVs are the following: (A) Copious OV replication, followed by damage of lysosomes, autophagy, and cytolysis; (B) OV alters the permeability and mitochondrial metabolism, which is followed by cytolysis; (C) OV determines the tumor cell stress response, triggering the JNK pathway and caspase cascades, which is followed by cytolysis; (D) Protein on OV surface binds to TRAILR1 and TRAILR2 receptors, activating the TRAIL-mediated apoptosis (BioRender.com).

Figure 3

The cold TME contains stroma and immunosuppressive cells. OVs cause cell death. Remodeling of suppressive immune and metabolic environment to hot TME. CAF, cancer-associated fibroblast; DC, dendritic cell; IFN, interferon; IL, interleukin; MDSC, myeloid-derived suppressor cells; NK, natural killer; OV, oncolytic viruses; TME, tumor microenvironment; Treg, regulatory T cells (Biorender.com).

Figure 4

Antiangiogenic mechanisms induced by oncolytic viruses (OVs). (A) OVs determine the recruitment of neutrophils and the development of microthrombosis and ischemia, followed by apoptosis. (B) Engineered virus can induce direct lysis of endothelial cells. (C) OVs can modulate transcriptional factors, decrease the production of IL8, and, consequently, stimulate apoptosis. (D) OVs interact with angiogenic proteins and downregulate the expression of VEGF.(BioRender.com).

Figure 5

Immunogenic cell death pathways induced by natural oncolytic viruses (OVs). Some natural OVs, including Newcastle disease viruses (NDVs), coxsackieviruses (CVs), measles viruses (MVs), herpes simplex viruses (HSVs), vaccinia viruses (VVs), adenoviruses (Ads), semliki forest viruses (SFVs), and parapoxviruses (ORFVs) can induce a specific mode of immunogenic cell death. NDV, HSV, and Ad can induce multimodal cell death, modulating the exposure of damage-associated molecular patterns in dying malignant cells, followed by recruitment of innate immune responders and triggering of a strong immune response. VV induces necroptosis, and CV, MV, SFV, and ORFV induce immunogenic apoptosis (BioRender.com).