Cancer continues to be one of leading causes of death and remains a major threat to human health. The World Health Organization predicts the rate of cancer incidence and mortality will continue to rise in the next 20 years [1]. The effects of traditional therapeutic modalities such as surgical resection, chemotherapy, radiation therapy, and recently developed immunotherapy are not optimal despite recent improvements. Thus, there is a critical need for novel anti-tumoral strategies.

Vaccines have become an important milestone in the development of the field of immunology and success in healthcare. The basic premise lies with inoculation of an attenuated form or noninfectious portion of the infectious organism into the body to elicit an immune response. Vaccines grant protective immunity to the body by program the immune system to recognize and target these foreign invaders. When exposed to the nonimpaired version of a virus, the immune system is then able to respond quickly and efficiently to subdue the virus, thus preventing major infection [2]. As a result, vaccine development has been critical in drastically reducing the number of deaths due to smallpox, yellow fever [3], measles, mumps, rubella, and varicella [4]. Certain viruses have been recognized for the ability to target tumor cells. These oncolytic viruses (OVs) tend to use live and infectious viruses and have become a topic of interest in the arena of cancer therapeutics because of their ability to induce selective cell death and specific anti-tumor immunity. In this review, we summarize and integrate what has been published in the literature in terms of the wide diversity of OVs, discuss the challenges in oncolytic viral therapy, and suggest how modification and implementation of OVs in conjunction with traditional cancer therapies may enhance the overall success of adjuvant treatments.

OVs are a type of cancer therapy where viruses are selected for their oncolytic capacity. Often, these viruses are attenuated through alterations in the viral genome that allow for reduced cytotoxicity toward non-cancerous cells and conditional replication in cancer cells. Alternatively, OVs may also be selected for through mutliple passages in tumor tissues. Key viral genes needed for virulence are substituted with genes that encode proteins to specifically target tumor cells. Thus, this strategy prevents viral targeting of nonmalignant tissues and restricts viral replication to only within tumor cells [5,6]. Moreover, use of engineered viruses in virotherapy often comes with a question of potential insertional mutagenesis where the viral genome integrates itself into the host’s genome [7]. However, OVs undergo multiple preclinical studies which assess for efficacy and safety before application in humans as demonstrated by Duerner et al.’s (2008) study of conditionally replication-competent murine leukaemia virus [8]. Despite the low possibility of genomic integration and detrimental impact in the clinical outcome, concrete long term safety data regarding administration of these engineered viruses in humans is needed as more therapeutics are implementing these viruses in both oncology and non-oncology clinics [7].

This selective elimination of cancer cells often depends on the viral strain, cancer type, tumor microenvironment (TME), and host immune system. OVs are intended to preferentially target cancer cells by exploiting unique extracellular surface markers on cancer cell, thus gaining entry into the cell. Commonly overexpressed surface markers in tumor cells are CD46, CD155, and integrin α2β1, which serve as receptors for measles virus, poliovirus, and echovirus respectively [9,10]. Cancer cells often have specific mutations (i.e., aberrations with in BCL-2, EGFR, PTEN, RAS, RB1, TP53, and WNT) that allow for unregulated cell proliferation. However, these mutations may also predispose the tumor cells to viral infection and subsequent cytotoxic elimination [11-13]. Nevertheless, normal cells often induce interferon (IFN) expression in response to viral infection. However, due to the inability of cancer cells to to induce type 1 IFN signaling [11], OVs are able to freely replicate within cancer cells, subsequently inducing oncolysis and release of viral progeny to continue the infection cycle. In addition, OVs may be armed to express immunostimulatory cytokines/chemokines (e.g., tumor necrotic factor (TNF), Interferon (IFN) α, and granulocyte-macrophage colony-stimulating factor (GM-CSF)), which allow the viruses to elicit a strong host immune response [3,4].

OV treatment begins with inoculation of the virus followed by viral replication which generates excessive virus-induced damage, compromising the integrity of cancer cells and results in oncolysis [11]. OV replication has also been found to promote strong anti-tumor immunity through the induction of immunogenic cell death (ICD), which releases tumor antigens (TA), damage-associated molecular patterns (DAMPs), OV-derived pathogen-associated molecular patterns (PAMPs), and inflammatory cytokines to activate and recruit both innate and adaptive immune cells [14,15]. PAMPs function to alert the immune system of the presence of pathogens [16], while DAMPs function to bring awareness to tissue trauma by binding to corresponding receptors on dendritic cells to induce T-cell activation and strongly influences the immune balance in the TME [17,18].

Furthermore, some OVs trigger the anti-tumor response without viral replication-mediated oncolysis. Binding of OVs to the tumor cell triggers activation of an antiviral immune response, where PAMPS trigger secretion of cytokine, and DAMPS to recruit immune cells to the area. Thus, this alternative pathway also promotes an anti-tumor immune response (Figure 1) [19,20]. Therefore, OVs are a feasible option to target notoriously non-immunogenic “cold” tumors, which are known to inhabit a TME that suppresses immune responses and T cell invasion by effectively stimulating both the innate and adaptive immune system. Many of these cold tumors are also non-reponsive to current available immune checkpoint inhibitors and demonstrates in crutial need improvement in the efficacy of cancer immunotherapy [21,22].

Figure 1. Overview of the pathway in oncolytic virotherapy. Inoculation introduces the oncolytic virus (OV) to the tumor. OVs bind to specific extracellular surface markers that are solely expressed on tumor cells, gaining entry into the cell. Hijacking the host machinery, the OVs rapidly replicate and induce oncolysis, releasing viral progeny, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), chemokines, and cytokines. Released viral progeny continue the oncolytic cycle by binding to neighboring tumor cells, while the other factors work to recruit various types of immune cells (e.g., CD4+ T cells, CD8+ T cells, and NK cells) to the tumor, allowing for tumor infiltration and enhanced eradication of malignant cells. Alternatively, some oncolytic viruses do not induce oncolysis, rather these viruses induce secretion of DAMPS and pro-inflammatory cytokines to recruit immune cells to target the tumor cells. Created with BioRender.com.

Oncolytic Virus Strains

Various OVs with anti-tumor properties have been explored, including both DNA and RNA viruses (Table 1). It is important to note that not all DNA/RNA viruses are oncolytic viruses. The important factor that separates oncolytic viruses from other genetically altered viruses for treatment purposes is that OVs are able to replicate and induce cell lysis, hence their name. Genetically altered viruses such as certain adenovirus agents serve as viral vectors that simply deliver the gene(s) of interest, often tumor antigens, and are replication-defective (RD), which is a characteristic that aids in the safety of this treatment modality [23]. This is commonly implemented in vaccine development and has proven to provide effective protection with no serious adverse events such as clinical infection or shedding of the virus into the surrounding environment. This has been demonstrated in RD-recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO) and many other studies using adenoviral vectors as a vaccine platform [24].

From a biological perspective, DNA viruses demonstrate higher genome stability due to their high-fidelity DNA polymerases. Their larger genomes often allow for greater ability to incorporate larger transgene insertions without jeopardizing the capacity for viral infection and replication. Replication takes place in the nucleus. However, the large genome size impedes replication kinetics [25-27]. While DNA viruses can encode proteins that protect viral nucleic acid detection [27], these viruses are also able to a elicit strong antiviral responses which can aid in anti-tumor immunity. The caveat remains that high neutralizing antibodies (nAbs) may limit viral replication, thus hindering viral spread [28]; however there have been reports tjat oncolytic viruses are able to replicate efficiently even in the presense of nAbs that target the backbone virus [29]

On the other hand, RNA viruses such as Newcastle disease virus (NDV), poliovirus, and reovirus have limited genomic packaging capacity but can be more immunogenic. Some viruses may encode proteases that cleave RNA virus sensors, which inhibits the antiviral response [27]. Moreover, replication of RNA viruses takes place in the cytoplasm and demonstrate rapid proliferation. Their high mutation rates introduces new genentic variation due to the low-fidelity RNA polymerase [25,27]. This allows for rapid evolution toward a beneficital oncolytic phenotype but also may cause divergence from this desired characteristic. The issue of genetic stability has also been proposed as a possible advantage for “personalized” targeted therapy, where multiple optimized virus variants can promote tumor clearance even in the presence of antiviral immunity [30]. Thus, the use of RNA viruses can be a double-edged sword, thus calling for a judicious design in the construction of OVs and study designs.

Common examples of oncolytic DNA viruse include vaccinia virus (VV), adenoviruses, and herpes simplex virus (HSV). VV is a double-stranded DNA (dsDNA) virus that infects and replicates within the cytoplasm of mammalian cells [31]. There have been various vacccina virus agents being studied. Pexa-Vec is an oncolytic VV with inactivated thymidine kinase (TK) gene that is replaced with a transgene that expresses human GM-CSF and β-galactosidase [32]. Pexa-Vec has been evaluated in the treatment of hepatocellular carcinoma (HCC) and colorectal cancer [31,33, 34]. Moreover, GL-ONC1 (VV with Ruc-GFP, β-glucuronidase, and β-galactosidase transgene insertions), vvDD (VV with deletion of the vaccinia growth factor and TK genes), and TBio-6517 (VV that expresses Flt3 ligand, the cytokine IL-12, and an antibody targeting CTLA4) are under clinical investigation [35-37].

Adenovirus is a dsDNA virus. Onyx-015 (lontucirev) was the first recombinant adenovirus to be tested in humans and features viral attenuation and conditional replication due to deletion of the E1B locus, which encodes for 55 kD E1B protein [38]. Onyx-015 has been discontinued midway through phase III trials looking at head and neck cancer in China despite the possible success in meeting the primary endpoint based on the interm report of efficacy and safety [39]. Second-generation adenoviruses such as DNX-2401 (tasadenoturev) have demonstrated success in treating glioblastomas [40]. The 24 base pair deletion of the E1A gene prevents DNX-2401 from replicating in cells that maintain normal retinoblastoma (Rb) pathways and selectively targets cancer cells with Rb pathway abnormalities [41]. DNX-2401 has shown success in treating malignant gliomas and has been granted fast track orphan drug designation by the US Food and Drug Administration (FDA) in malignant glioma in 2014 [40]. Currently, combination with immune checkpoint inhibitors are being pursued. Additional examples of oncolytic adenoviruses under clinical investication include enadenotucirev (chinerix Ad11p/Ad3 oncolytic adenovirus with a 25 bp deletion of E4 and 2444 bp deletion in E3ORF), LOAd703 (a serotype 5 adenovirus with serotype 35 fiber and knob and encodes trimerized membrane-bound CD40L and 4-1BBL), and ONCOS-102 (a modified sertotype 5 adenovirus with a serotype 3 knob, insertion of the GM-CSF transgene, and a 24 bp deletion of the Rb binding site of the E1A gene) [42-45].

Herpes simplex virus (HSV), specifically HSV-1 and HSV-2, is a dsDNA virus that naturally infects humans [46,47]. HSV oncolytic therapy has been applied to the treatment of melanomas, gliomas, and colorectal cancer [48,49]. HSV1716, a mutant that lacks the ICP34.5 neurovirulence gene, selectively targets and replicates in human glioblastoma cells [50]. NV1020 is a mutant HSV with deletions of a 15-kb region at the UL/S junction including the U_L56 gene and further attenuation by a 700-bp deltion encompassing the TK gene and the U_L24 promotor [51, 52]. Reinsertion of viral HSV-1 TK gene enables control of NV1020 infection with TK-converted prodrugs like acyclovir. Weekly hepatic arterial infusion of NV1020 was noted to stabilize the liver metastasis in 50% of patients with heavily treated colorectal cancer at the optimal biological dose of 1x10⁸ plaque-forming unit (PFU) [49]. Other HSV-based OVs that are under clinical trials include G207 (an HSV-1 strain with deletion of the neurovirulent _γ134.5 gene and insertion of β-galactosidase to inactiave U_L39 gene), ONCR-177 (an HSV-1 agent with a mutant UL37 gene, tissue-specific miRNA attenuation, and insertion of five transgenes for IL-12, FLT3LG, CCL2, and antagonists against PD-1 and CTLA-4), OH2 (genetically modified HSV-2 which expresses GM-CSF), and RP1 (an HSV-1 agent that expresses GM-CSF) [53-57].

NDV is a single-stranded RNA (ssRNA) virus that naturally infects avian hosts (poultry) [58,59]. One of the most studied strains of NDV is MTH-68/H, which has been applied to treatment of epithelial tumors as well as high-grade glioma [48, 60, 61]. Another NDV agent, LaSota, is a lentogenic strain of lower pathogenicity. LaSota has been studied in vitro using HPV E6/E7 expressing TC-1 cells that serves as a cervical cancer model and showed that the tumor cells had suppressed growth by OV induced apoptosis [61].

Poliovirus is a ssRNA virus that naturally targets neurons, which makes this an effective vehicle for glioma-targeted oncolytic therapies. Poliovirus infection is limited to human and old-world primates due to viral binding with the poliovirus receptor Nectin-like molecule 5 (Necl-5) or CD155 in order to enter host cells [62,63]. Recombinant virus PVSRIPO is an attenuated chimera created from non-pathogenic strains of rhinovirus and type 1 poliovirus vaccine and has been studied in malignent glioma and melanoma [64,65]. The poliovirus internal ribosomal entry site (IRES) has been replace with that of rhinovirus [66]. Deletion of the poliovirus IRES attenuates neurovirulence and selects for conditional replication in tumor cells, specifically binding to CD155 which has been found to be highly upregulated in many cancer types [63,67].

Respiratory enteric orphan virus (reovirus) is a nonenveloped, double-stranded RNA (dsRNA) virus that is able to infect a wide range of mammalian hosts [68], including bats, humans, minks, and pigs [69]. Reovirus is mostly nonpathogenic in humans and has demonstrated preferential replication within cancer cells that express a constitutively activated Ras pathway. However, the virus does not affect nonmalignent cells without Ras activation [70]. Pelareorep is a shortened form of reovirus that was given an orphan drug status in 2015 by the FDA and the European Medicine Agency (EMA) for the treatment of malignant gliomas, ovarian cancer, and pancreatic cancer, which are considered as Ras-activated tumors [71]. Since then, reovirus has also been used to treat melanomas, breast cancer, and head and neck squamous cell carcinoma [72-74].

Table 1: Comparison between DNA and RNA virus characteristics.

Implementation of OVs requires careful evaluation as there are multiple factors that must be taken into account. Different methods of inoculation have benefits and drawbacks with viral therapy. Moreover, the tumor extracellular matrix (ECM) must be accounted for as an important factor as well as the tumor stroma. Cell populations including cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) can dramatically hinder oncolytic virotherapy efficacy.

Oncolytic Virus Administration

OVs can be administered either through direct inoculation into the tumor bulk or systemic injection, which includes intravenous (IV) or intraarterial (IA) injections [101]. There are benefits and challenges with both methods of administration. Direct intratumoral (IT) inoculation has been the most successful, as shown with FDA approved fast tracking of T-VEC. Direct IT inoculation maximizes the concentration of virus at the site of the lesion and thus induces a strong immunological response. However, this method is limited by tumor accessibility. Deep-seated tumors or those that are located in sensitive locations restrict the applicability and feasibility of IT inoculation as such invasive procedures carry a risk of injuries and complications. Moreover, other limitations include poor intratumoral retention due to viral dissemination into the bloodstream, limited viral dispersion in tumor tissues, and adverse inflammatory responses [102].

In contrast, systemic therapy utilizes the body’s vascular system to circulate OVs throughout the body similar to the delivery of chemotherapy or other anti-cancer agents. Likewise, there are a few hypothesized disadvantages associated with indirect inoculation. The first area of concern lies with systemic toxicity, whether the dosage of OVs may result in unanticipated off-tumor tissue or organ damage. Another major concern is immune clearance or the neutralization of OVs by the B cell generated antibodies, which interferes with internalization of the virus and dramatically abates the viral titer that ultimately reaches the tumor site [101,103].

This brings up the issue with seropositivity to the backbone virus, which is especially important viruses that are highly prevalent in the community. For example, there are multiple reports confirming high prevalence of seropositivity against human adenovirus (hAdV) infections throughout the world, including the United States, Australia, Japan, and the Philiphines. Ye et al. (2018) looked at the prevalence of nAbs to HAdV type 4 and type 7 in a group of volunteers from Hunan Province, China. The seropositivity rates for HAdV4 and HAdV7 nAbs were 58.4 and 63.8% respectively [104]. Thus, it can be predicted that a large portion of worldwide populations in areas with a history of HAdV infection contain high seropositivity for HAdV nAbs. The issue remains that seropositivity limits viral replication [105]. Neutralizing antibodies would bind to the OVs and inhibit cellular receptor binding [103,106]. Thus, decision about the choice of viral strain and the mode of administration should be made with careful consideration to preexisting immune responses.

Most of the literature agrees that suppression of humoral immunity is essential for systemic administrated oncolytic virotherapy [107]. The IFN pathway, specifically IFN-α, antagonizes OVs by reducing viral replication and stymying virus-mediated apoptosis [108]. Since cancers cells often lack a type 1 IFN response, these cell are more permissive to OV infection and replication [59].

Attempts have been made to protect OVs from the innate and adaptive immune system, specifically the humoral response with the use of IFN response inhibitors to enhance viral replication and efficacy of oncolysis. However, there have been safety concerns regarding the use of IFN antagonists. Saren et al. (2017) noted that treatment of glioblastoma bearing mice with Semliki Forest virus equipped with vaccinia virus-encoded type 1 IFN decoy receptor B18R controlled tumor growth but also induced severe neurotoxicity as the virus disseminated and replicated in healthy brain tissue [109].

Another method to protect OVs involves the use of genetically engineered protective coatings composed of chemical polymers, cell-derived nanovesicles, and liposomes that serve as a more direct method of overcoming the humoral immune response [110-112]. These protective coatings reduce immune recognition of the virus, thus limiting the production of nAbs against the OVs. The addition of tumor-targeting ligands can also help the OVs hone in on the tumor. The major concern with protective coatings is the practicality of the design. Protection of OVs increase the viral titer that reaches the tumor; however, the coatings may undermines the ligand-receptor interactions between OVs and tumor cell receptors resulting in reduced internalization of OVs. Moreover, additional drawbacks include issues with high production costs and limitations with large-scale transport of OVs [107].

Another feasible method is the use of carriers, either patient-derived cellular carriers (i.e., OV-infected cells that are injected back into the patient) or engineer carriers (i.e., nanoparticles). A wide range of cell types can be used as cellular carriers: endothelial cells, mesenchymal stromal cells, T-cells, and even tumor cells. However, there are safety concerns using certain cell types. Even though the patient’s own tumor cells are attractive from an immunologic standpoint, tumor cells or transformed cells should be studied with proper safety measurements. Furthermore, mesenchymal stem cells or neuronal stem cells demonstrate tumor tropism, allowing delivery of OVs throughout the body. However, such cell types are known to evade the immune system by allowing immune escape of tumor cells. The use of biodegradable nanoparticles is also gaining traction for compact delivery of viral antigens and the wide selection of nonmetal and metal-based compositions to maximize delivery of OVs [107]. Liposomal nanoparticles have demonstrated a high degree of biocompatibility with the host’s body and can be rapidly degraded by macrophages, making them a favorable candidate as a OV carrier [113].

Challenges with Tumor Structure

Moreover, physical barriers such as the tumor stroma may prevent chemotherapy, tumor infiltrative effector cells, and OVs from effectively approaching tumor cells [114,115]. The tumor stroma is composed of non-tumor cells and structural components of the tumor tissue. Tumor cells are able to secrete cytokines to suppress certain anti-tumor functions of immune cells, while the stromal cells construct the desmoplastic stroma barrier, which physically impedes immune infiltration [116]. The stroma encapsulates the dense ECM, CAFs, TAMs, and tumor vasculature; all of which reinforce tumor resistance against the host’s immune system [117-119].

The ECM is generated by CAFs and poses the greatest barrier as it composes most of a tumor’s mass, creates an impenetrable barrier around the tumor, and undermines immune invasion and anti-tumor drug efficacy [119]. The denseness of the ECM also creates a paucity of oxygen and nutrients, which tumor cells exploit to induce activation of metabolic stress-related signaling pathways. Activation of these signaling pathways allows tumor cells to sculpt the TME to better suit their needs. For example, vascular endothelial cells (VECs) can dedifferentiate into tumor endothelial cells (TECs), which demonstrate enhanced proliferation, augmented migration capabilities, and facilitation of angiogenesis [120,121]. Another effect is the activation of drug efflux pumps and induction of senescence, both of which enhance tumor resistance against anti-cancer agents such as chemotherapy [119]. CAFs recruit myeloid-derived suppressor cells (MDSCs) and Tregs to create an immunosuppressive environment [122]. M2 TAMs have been shown to secrete TGF-β, which stimulates secretion and cross-linking of collagen, bolstering and fortifying the ECM [114,123].

Some studies have investigated methods to target the tumor stoma. For example, OVs expressing proteases such as matrix metallopeptidases (MMP)-9 can degrade ECM components. Sette et al. (2019) demonstrated that treatment of glioblastoma multiforme (GBM) with OV-derived HSV armed with MMP-9 increased viral invasion of GBM stem-like spheroids and improved survival of tumor-bearing nude mice [124]. In addition, OVs can be equipped with tissue inhibitor metalloproteinases 1-4 (TIMPs 1-4), which regulate proteolytic activity of MMPs and prevent rearrangement of the ECM [125]. Another method is to repolarize anti-inflammatory M2 TAMs into the pro-inflammatory M1 phenotype. M2 TAMs promote tumor proliferation through immune modulation and tolerance in addition to the recruitment of Tregs [126,127]. On the other hand, M1 TAMs secrete proinflammatory cytokines (e.g., IL-6, IL-12, and TNF-α) and reactive oxygen species (ROS) in order to enhance immune recruitment and function against malignant cells [128]. Rao et al. (2020) demonstrated the use of genetically engineered cell membrane-coated magnetic nanoparticles that triggers M2-M1 TAM repolarization demonstrated inhibition of tumor proliferation, reduced metastasis, and improved survival of mice with triple-negative breast cancer [129].

Overall, the complexity of the tumor stroma and the various components work in tandem to create an immunosuppressive environment and a physical barrier against not only tumor infiltrating cells but also anti-cancer agents. OVs can influence the TME to convert the pro-tumor TME into an anti-tumor environment, but there still is room for improvement for the strategies described above. Figure 2 shows an overview of This highlights the need for novel approaches in OV development and more research in targeting both the tumor and the surrounding stroma.

Given the compiled efforts in the field of oncolytic virotherapy, there are multiple ongoing clicical trials that investigate OVs in a variety of cancers, including breast, gastrointestinal, skin, and pancreatic cancers. The most common OV candidates include vaccinia virus, HSV, and adenovirus. A subset of ongoing clinical trials solely focus on determining patient response to OV single agent therapy, while the vast majority of trials use a combination approach (Figure 2), often pairing OV treatment with chemotherapy, monoclonal antibodies, or radiotherapy (Table 2, data was collected from clinicaltrials.gov in May 2022). However, there is a critical need for studies on accurate biomarkers to tailor and optimize therapeutic options that combine various treatments for specific patients as disease characteristic may differ across different patients.

Figure 2: Strategies to Overcome Cancer Resistance to Immunotherapy using Oncolytic Viruses. Mechanisms of resistance to currently available immune checkpoint inhibitor therapies and other immunotherapy remain multifactorial. Oncolytic viruses have potential to help overcome primary or secondary resistance to immunotherapy independently or in combination with other immune modulatory agents.

Table 2: Select ongoing clinical trials involving oncolytic virus and other anti-cancer therapies.

OVs have come to the forefront of immunotherapy, offering a wide range of viruses as a backbone which can be genetically engineered to selectively target and replicate within tumor cells, while leaving normal cells unscathed. Ultimately, cell lysis releases various factors that attract immune cells toward the tumor while viral progeny infects neighboring tumor cells to continue the oncolytic cycle. The conditional replication of OVs make them an appealing therapeutic option. However, the administration of OVs must overcome various barriers such as viral neutralization by the humoral immune response and the hostile TME, which requires further investigation. Some studies have looked into using protective coatings or cellular carriers to overcome viral neutralization and enhance delivery of OVs to the tumor site. Lastly, a review of clinical trial registries for ongoing clinical trials in oncolytic virotherapy reflects a profound interest in the involved biomedical community especially in combination approaches with conventional cancer treatments such as surgery, chemotherapy, radiation, as well as novel immune modulators.

Future studies need to verify the long-term safety and efficacy of incorporating OV therapy. Additionally, further research is needed to develop a strategy that can target cancer heterogeneity while ensuring proper receptor binding for viral entry in the setting of rapidly evolving cancer cells which may need to involve precision medicine to offer a more personalized approach for patients.

In summary, oncolytic virotherapy has secured its role to support cancer immunotherapy as the fourth pillar of cancer treatment, and research will continue to expand on the utilities of OV as an important element in multimodality approaches.

Author Contributions: Conceptualization: C.X; information collection, X.W and H.M.M; original draft preparation, X.W; writing-review and editing; X.W, H.M.M, C.X, and J.L. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by the Physician-Scientist Early Investigator Program at CCR of NIH/NCI to CX (ZIA BC 011888).

Conflicts of Interest: The authors declare that they have no conflict of interest.

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