Next Article in Journal
Decrypting the Immune Symphony for RNA Vaccines
Previous Article in Journal
Therapeutic Vaccines for Non-Communicable Diseases: Global Progress and China’s Deployment Pathways
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Oncolytic Herpes Simplex Virus Therapy: Latest Advances, Core Challenges, and Future Outlook

State Key Laboratory of Drug Regulatory Sciences, National Institutes for Food and Drug Control, Beijing 102629, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Vaccines 2025, 13(8), 880; https://doi.org/10.3390/vaccines13080880 (registering DOI)
Submission received: 9 July 2025 / Revised: 16 August 2025 / Accepted: 18 August 2025 / Published: 20 August 2025

Abstract

Oncolytic virus (OV) immunotherapy, particularly with oncolytic herpes simplex virus (oHSV), has become a promising new strategy in cancer treatment. This field has achieved significant clinical milestones, highlighted by the FDA approval of Talimogene laherparepvec (T-VEC) for melanoma in 2015 and the approval of Teserpaturev/G47Δ for malignant glioma in Japan in 2021. This review synthesizes the key preclinical and clinical advancements in oHSV therapy over the last decade, critically analyzing the core challenges in target selection, genetic modification, administration routes, and targeted delivery. Key findings indicate that arming oHSV with immunomodulatory transgenes, such as cytokines and antibodies, and combining it with immune checkpoint inhibitors are critical strategies for enhancing therapeutic efficacy. Future research will focus on precision engineering using CRISPR/Cas9, the development of novel delivery vehicles like nanoparticles and mesenchymal stem cells (MSCs), and biomarker-guided personalized medicine, aiming to provide safer and more effective solutions for refractory cancers. This review synthesizes oHSV advances and analyzes novel delivery and gene-editing strategies.

1. Introduction

Oncolytic viruses (OVs) are a class of viruses that can specifically infect and kill tumor cells, possess strong replication capabilities, and can stimulate the body to produce a robust anti-tumor immune response. The concept of using viruses to treat cancer dates back to the early 20th century, with initial clinical observations of improvement in 7 of 22 patients with lymphogranuloma reported in 1912 [1]. In 1949, Moore et al. [2] first discovered in a mouse sarcoma model that the Russian Far East encephalitis virus could selectively infect and kill tumor cells. However, the modern era of oncolytic virotherapy was launched by the advent of genetic engineering. A pivotal moment occurred in 1991 when the first genetically engineered Herpes Simplex Virus type 1 (HSV-1), with its thymidine kinase (TK) gene knocked out, was successfully used to treat mouse glioma [3], marking the beginning of the oHSV field. Among the various OVs being developed, oHSV has emerged as a leading platform for both research and clinical application. Its prominence was cemented in 2015 when the U.S. Food and Drug Administration (FDA) approved Talimogene laherparepvec (T-VEC), an oHSV-based therapy, for the treatment of advanced melanoma [4]. This was followed by the approval of another oHSV, Teserpaturev/G47Δ, in Japan in 2021 for treating malignant glioma, further validating the potential of oHSV in combating solid tumors [5]. In 2024, nanoparticle-enhanced G207 (FA-PEG conjugate) has shown increased tumor targeting in preclinical models [6]. In 2025, MSC-based oHSV delivery demonstrates BBB penetration for brain metastases in clinical trials [7]. These successes have spurred significant investment and research into optimizing oHSV design and application.
This review first explores oHSV’s mechanisms and advantages, then synthesizes preclinical and clinical progress, addresses technical challenges in delivery and administration, and concludes with future directions for personalized therapy.
To date, oncolytic virus therapy has become a research hotspot in the field of cancer treatment (Figure 1). Currently, five oncolytic virus drugs have been approved for marketing globally (Table 1).

2. Mechanisms and Advantages of oHSV

2.1. Core Anti-Tumor Mechanisms

The anti-tumor mechanisms of oncolytic viruses primarily include the following three (Figure 2): ① Oncolysis: Oncolytic viruses exhibit tumor tropism and can selectively replicate within tumor cells, leading to direct cell lysis. The progeny infectious viruses released after lysis can continue to infect and kill tumor cells [11]. Furthermore, tumor cell lysis releases substances such as tumor-associated antigens (TAAs), Pathogen-Associated Molecular Patterns (PAMPs), and Damage-Associated Molecular Patterns (DAMPs) [12], triggering further immune responses. ② Anti-tumor immune response: Through genetic engineering, one or more exogenous genes (e.g., chemokine genes, immunostimulatory cytokine genes, tumor-associated antigen genes) can be inserted into the oncolytic virus genome. The tumor cells then process and translate these genes into exogenous protein molecules. The expressed chemokines (e.g., CXCL9, CXCL10, CXCL11, etc.) [13] can induce lymphocyte infiltration into tumor tissues. The expressed immunostimulatory factors (e.g., IL-12, IL-15, TNF-α, GM-CSF, etc.) [14] further activate lymphocytes, inducing a strong anti-tumor immune response in the body. The produced tumor-associated antigens [15] can be taken up, processed, and presented by Antigen Presenting Cells (APCs), activating T cells and causing a systemic anti-tumor immune response. This is an important mechanism by which oncolytic virus therapy can exert a killing effect on “distant” tumors. ③ Inhibition of angiogenesis: While not an intrinsic property of wild-type HSV, oHSV can be engineered to inhibit tumor angiogenesis. This is achieved by inserting anti-angiogenic genes, such as those for thrombospondin-1 (TSP-1) [16], angiostatin [17], or endostatin [18,19], into the viral genome. Studies have shown [20] that oncolytic viruses can enter vascular endothelial cells and inhibit intra-tumoral angiogenesis, preventing tumor cells from obtaining the large amounts of nutrients required for growth, thereby achieving growth inhibition.

2.2. Unique Advantages of HSV

Based on the type of genetic material, the classification and characteristics of oncolytic viruses are shown in Table 2. Herpes simplex virus (HSV) is a type of herpesvirus belonging to the Alphaherpesvirinae subfamily [21] and is one of the main viruses currently used in the development of oncolytic virus therapies. The structure of HSV consists of a surface envelope, a proteinaceous tegument layer, a nucleocapsid, and a DNA core [22]. Its genome is composed of two unique long (UL) segments and two unique short (US) segments linked together, with terminal repeat sequences. It is classified into two serotypes, HSV-1 and HSV-2 [23]. The HSV-1 genome is 152 kb in length, and the HSV-2 genome is 154 kb in length, with a nucleic acid sequence homology of up to 50% [24].
Compared to other viral vectors, HSV possesses several distinct advantages for oncolytic therapy: ① Large transgene capacity: HSV is an enveloped virus with a complex structure, typically capable of accommodating exogenous genes of approximately 40–50 kb in length, with a maximum capacity of about 100 kb [25]. It is currently the viral vector with the largest capacity, making it possible for HSV to simultaneously carry more and longer immunomodulatory molecule genes. ② High replication efficiency: The virus enters host cells via membrane fusion or endocytosis, releases its DNA into the nucleus, and utilizes the host cell machinery for transcription and replication to complete its life cycle, exhibiting extremely high replication efficiency. ③ Broad tropism: HSV can infect almost all human tumor cells, demonstrating a broad infection spectrum. ④ Blood–brain barrier (BBB) penetration: While the BBB in the body can block most viruses, HSV can attach to and penetrate the BBB, enabling gene delivery to the nervous system. This provides a unique advantage for the treatment of nervous system diseases, especially central nervous system tumors [26]. Compared to other oncolytic viruses (Table 2), HSV holds a prominent position in the development of oncolytic virus therapies due to its unique biological characteristics and modification potential, making it the focus of this review.
Table 2. Classification of oncolytic viruses.
Table 2. Classification of oncolytic viruses.
TypeVirus TypeGenome SizeTransgene CapacityInfection ReceptorCell Entry MechanismReplication SiteAdvantages
dsDNAHerpes Simplex Virus (HSV) [27]150 kbHighHVEM, nectin1, nectin 2 [28]Endocytosis; PenetrationNucleus and CytoplasmLarge genome, high manipulability
Adenovirus (Adv) [29]36 kbMediumCAR, CD46EndocytosisNucleus and CytoplasmEasy to prepare high-titer virus samples; easy genome manipulation
Vaccinia Virus (VV) [30]190 kbHighGAGs, EFCMembrane fusion; EndocytosisCytoplasmHigh virus propagation efficiency; short life cycle; allows insertion of large fragments
dsRNARespiratory Enteric Orphan Virus (REO Virus) [31]16~27 kbHighJAM-AReceptor-mediated endocytosisCytoplasmSuitable for intravenous injection; no dose-dependent toxicity
ssDNAParvovirus [32]5 kbLowCyclin A, E2FReceptor-mediated endocytosisNucleusTumor tropism, high replication efficiency
(+) ssRNACoxsackievirus (CVA) [33]7.5 kbLowCAR, ICAM1, DAF [34]MicropinocytosisCytoplasmSuitable for intravenous injection
Seneca Valley Virus (SVV) [35]7 kbLowANTXR1 [36]Receptor-mediated endocytosisCytoplasmNon-pathogenic to human
Poliovirus (PV) [37]7.5 kbMediumCD155Receptor-mediated endocytosisCytoplasmInfection receptor widely expressed in malignant tumors
(−) ssRNAMeasles Virus (MeV) [38]16 kbLowSLAM, CD46Membrane fusionCytoplasmTumor tropism
Sendai Virus (SeV) [39]15 kbLowSialic acidMembrane fusionCytoplasmTumor tropism; high safety
Newcastle Disease Virus (NDV) [40]15 kbLowSialic acidEndocytosis; pH-independent fusionCytoplasmNon-pathogenic to humans
Vesicular Stomatitis Virus (VSV) [41]11 kbLowLDLREndocytosisCytoplasmShort life cycle; non-pathogenic to humans
dsDNA: double-stranded DNA; dsRNA: double-stranded RNA; ssDNA: single-stranded DNA; (+) ssRNA: positive-sense single-stranded RNA; (−)ssRNA: negative-stranded single-stranded RNA; HVEM: herpesvirus entry mediator; CAR: coxsackie adenovirus receptor; GAGs: glycosaminoglycans; EFC: entry fusion complex; JAM-A: junctional adhesion molecule-A; ICAM1: intercellular adhesion molecule 1; DAF: decay-accelerating factor; ANTXR1: anthrax toxin receptor 1; SLAM: signaling lymphocytic activation molecule; LDLR: low-density lipoprotein receptor.

3. Research Progress

3.1. Preclinical Advances

As an ideal viral strain for the development of oncolytic virus therapy, recombinant HSV is widely used in cancer immunotherapy. The basic strategy involves modifying or deleting key genes in the HSV genome that affect viral infection and replication to improve targeting and safety and introducing exogenous genes to induce local and systemic immune responses to enhance efficacy. Currently, the main types of genetic modifications include cytokine genes, tumor suppressor genes, anti-angiogenic factor genes, tumor antibody-associated genes, and viral native genes. Below, we will focus on the progress of different genetically modified HSV types in cancer treatment.

3.1.1. Cytokine Genes

Cytokines (CKs) are small-molecule polypeptides or glycoproteins synthesized and secreted by various tissue cells, possessing multiple biological functions such as regulating cell growth and participating in immune responses [42]. In 2015, following the FDA approval of the first genetically engineered HSV (T-VEC) for the treatment of advanced melanoma, a significant amount of research focused on inserting immunostimulatory cytokine genes into the HSV genome (Table 3). These modified HSVs demonstrated good anti-tumor effects and prolonged survival in preclinical animal models. The inserted cytokine genes mainly include GM-CSF [43,44,45,46,47,48,49,50,51], IL-12 [44,45,46,52,53,54,55,56,57], IL-15 [58,59], and OX40L [60] genes. These genes typically activate the local immune microenvironment, promote APC recognition and antigen presentation, stimulate CD4 + T and CD8 + T cell expression, and inhibit regulatory T cell (Treg) function, thereby enhancing the anti-tumor immune response.
Due to immune tolerance in the body, the efficacy of oncolytic viruses administered alone is often suboptimal. Combination therapy is an effective solution to address antiviral immune responses and immune tolerance issues [61]. Currently, treatment regimens often involve combination with immune checkpoint inhibitors (ICIs). Cytokine-modified oHSVs like T-VEC demonstrate robust immune responses, particularly when combined with checkpoint inhibitors, though optimal gene combinations remain under investigation. For example, OncoVEXmGM-CSF, RP1-19, OV-mOX40L, and R-123 have been explored in combination therapy with anti-CTLA-4 or anti-PD-1 antibodies [43,46,47,60]. This approach can alleviate the immunosuppressive tumor microenvironment and prolong the anti-tumor immune response, and the combined application exhibits a “1 + 1 > 2” anti-tumor effect, potentially even overcoming the problem of resistance to monotherapy.
Table 3. Preclinical research progress of genetically modified HSV in the last decade—cytokine genes.
Table 3. Preclinical research progress of genetically modified HSV in the last decade—cytokine genes.
Target GeneNameYearApplication MethodTumor ModelROAPreclinical Outcome
GM-CSFOncoVEX mGM-CSF [43] (HSV-1)2023CTLA-4 and PD-1 antibody; 1 × 106 PFUB16F10i.t.Reduced lung metastases, prolonged animal survival.
RP1-19 [47] (HSV-1)2020CTLA-4 and PD-1 antibody; 5 × 105 PFUTBP-B79i.t.Triple combination therapies (PD-1 and CTLA-4 blockade) enhanced antitumor effects.
OH2 [48,49,50,51] (HSV-2)20241 × 106 CCID50/mLU87, GL261i.c.Reduced tumor growth, prolonged animal survival.
20221 × 106, 1 × 105, 1 × 104 CCID50/mLCT26i.t.Significant antitumor activity and favorable tolerance
2022SIRPα antibody; 2 × 106 PFUCT26i.t.Induction of regional cytokine storm (mainly IL-6).
20192 × 107 CCID50/mLHT-29, CT26i.t.OH2 is safe.
OX40LOV-mOX40L [60] (HSV-1)2023IL-6 and PD-1 antibody; 2 × 106 PFUKPCi.t.Improved immunosuppressive microenvironment.
IL-12, IL-15, PD-L1BVG161 [59,62] (HSV-1)20205 × 105, 5 × 106 PFUCT26, A20, LS174Ti.t.Induced robust oncolysis and anti-tumor immune response.
2023Paclitaxel; 1 × 107 PFUEMT-6i.t.Reduced breast cancer growth and metastasis.
IL-12, IL-15/IL-15RαVG2025 [58] (HSV-1)20231 × 106 PFUA549i.t.Robust antitumor immune response.
IL-12/IL-15/GM-CSF/PD-1 antibody/IL-7, CCL19oHSV2-IL12, -IL15, -GM-CSF, -PD1v, -IL7 × CCL19 [44] (HSV-2)20221 × 107 PFU4T1, CT26i.t.Combination therapy had better anti-tumor effect.
IL-12, GM-CSFΔ6/GM/IL12 [45] (HSV-1)20211 × 107 PFUB16F10i.t.The anti-tumor immune response was enhanced.
R-123 [46] (HSV-1)2020PD-1 antibody; 1 × 108 PFUHER2-LLC1i.t.Reduced tumor metastasis.
IL-12R-115 [52,53] (HSV-1)20182 × 109 PFUHER2-LLC1i.p.Improved immunosuppressive microenvironment.
20192 × 106, 1 × 108 PFUmHGGpdgf-hHER2i.t.Reduced tumor growth, improved median survival time.
M002 [54,55,56,57] (HSV-1)20171 × 107 PFUSARCi.t.Improved immunosuppressive microenvironment.
20181 × 107 PFUX21415, D456, GBM-12, UAB1016i.t.Prolonged animal survival.
2014XRT; 1 × 107 PFUHuH6, G401, SK-NEP-1i.t.Reduced tumor growth, prolonged animal survival.
2013XRT; 1 × 107 PFUSK-N-AS, SK-N-BE, Neuro-2ai.t.Reduced tumor growth, prolonged animal survival.
C5252 [63] (HSV-1)20245 × 106 PFUU87i.t.Safe antitumor activity.
CXCL11, IL-12O-HSV1211 [64] (HSV-1)20231 × 107 PFUMC38i.t.Reduced tumor growth.
XRT: X-ray Radiation Therapy; SIRPα: Signal Regulatory Protein α; ROA: Route of Administration; i.t.: intratumoral injection; i.c.: intracerebral injection; i.p.: intraperitoneal injection.

3.1.2. Tumor Suppressor Genes

Tumor suppressor genes are a class of genes with potential cancer-suppressing effects, playing a negative regulatory role in cell growth, proliferation, and differentiation [65]. Exogenous introduction of PTEN [66,67,68] and P53 [69] genes can enhance the inhibitory effect of HSV on tumor cells (Table 4). HSV expressing PTEN (HSV-P10 [67], oHSV-P10 [68]) has been shown to regulate the PI3K/AKT and IL6/JAK/STAT3 signaling pathways, reduce PD-L1 expression in tumor cells, and decrease tumor immune escape. MH1004 [69], carrying the P53 gene, also showed results of inhibiting tumor growth and prolonging the survival of melanoma mice. Therefore, introducing tumor suppressor genes has also become a feasible option for developing oncolytic virus therapies.

3.1.3. Anti-Angiogenic Factor Genes

Anti-angiogenic factors can affect key signaling pathways that promote angiogenesis, downregulate the expression of vasoactive factors, and inhibit neovascularization [70]. In HSVs modified with thrombospondin-1 (TSP-1) [16], angiostatin [17], and endostatin [18,19] genes (Table 5), treatment resulted in reduced tumor angiogenesis, tumor hypoxia, and necrosis. In 2013, Toshiaki et al. [16] constructed an HSV investigational drug (T-TSP-1) by knocking the TSP-1 gene into the HSV-1 genome. The expressed TSP-1 demonstrated tumor vascular inhibition in the TMK-1 gastric cancer model, indirectly achieving tumor treatment. In 2012, Goodwin et al. [19] constructed an HSV containing another tumor angiogenesis inhibitor, endostatin (HSV-Endo). In a mouse lung metastasis L1C2 model, tumor vascular density was significantly reduced; unfortunately, the expression of endostatin appeared insufficient to achieve complete regression of lung tumors.

3.1.4. Tumor Antibody-Associated Genes

Exogenous introduction of tumor antibody-associated genes also shows unique advantages in developing oncolytic virus therapies (Table 6). Mechanisms of action include utilizing the antibody Fc segment to produce Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular Phagocytosis (ADCP) [71], enhancing the immune system’s ability to clear tumors and reducing immunosuppression [72]. In preclinical studies, exogenously introduced anti-Programmed Death-1 (PD-1) antibody genes in glioma [73], ovarian cancer [74], liver cancer [75], colon cancer [76,77], and cutaneous melanoma [77,78] models effectively reduced immunosuppression in the body and enhanced anti-tumor immune responses. For Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing colon cancer [79,80] and lung cancer [81,82,83] models, anti-HER2 antibody gene-recombinant HSV investigational drugs exert anti-tumor effects by inhibiting HER2 homo/heterodimerization, blocking pro-cancer signaling pathways [84], and recruiting immune effector cells (such as NK cells, macrophages) to produce ADCC effects. Anti-Epidermal Growth Factor Receptor (EGFR) antibodies can competitively bind to EGFR, reducing the secretion of immunosuppressive cytokines by tumor cells [85] (such as vascular endothelial growth factor, IL-10). HSV investigational drugs designed and modified accordingly [86,87] have shown good anti-tumor effects in glioblastoma models.

3.1.5. Viral Native Genes

Viral native genes have a significant impact on the safety and efficacy of genetically modified HSV (Table 7). The UL39 gene is involved in encoding ribonucleotide reductase, one of the enzymes necessary for viral replication in non-dividing cells [88]. Knocking out the UL39 gene in the HSV genome can significantly reduce the replication ability of HSV in normal cells, thereby improving safety. The HSV investigational drug G47Δ has a partial deletion of the UL39 gene, which restricts its replication in normal cells while retaining its high replication efficiency in tumor cells [89]. Preclinical studies have shown that G47Δ exhibits good anti-tumor effects in various solid tumor models of the nervous system [90,91,92,93,94,95,96]. Furthermore, combination therapy of G47Δ with chemotherapy drugs (temozolomide [91], axitinib [93]) or ICI drugs (anti-PD-1 and CTLA-4 antibodies [94,95]) has shown even better anti-tumor effects. The ICP34.5 gene is an important virulence factor of HSV, and its expression is closely related to neurotoxicity. Knocking out the ICP34.5 gene can reduce HSV neurotoxicity and minimize damage to the central nervous system. This strategy has been applied in the design of several HSV investigational drugs, such as HSV1716 [97,98,99,100,101,102,103], G207 [104,105], and Virus 16 [106]. The ICP47 gene is involved in regulating the antigen presentation process in host cells. Knocking out this gene can promote the presentation of tumor-associated antigens, enhancing the host immune system’s recognition and attack of tumors [107]. HSV investigational drugs with ICP47 gene knockout, such as G47Δ [90,91,92,93,94,95,96] and Virus 16 [106], have demonstrated more efficient anti-tumor killing effects in various tumor models. In addition to knocking out key genes involved in viral infection and replication, researchers have also focused on genes related to viral particle release and spread. The UL53 gene is involved in regulating the release of viral particles; the gK protein it encodes causes viral particles to accumulate within infected cells, limiting their release [108]. The HSV investigational drug HF10 [109,110,111,112,113,114], which overexpresses the UL53 gene, shows limited release of viral particles after infecting tumor host cells, thereby reducing damage to normal tissues. It has demonstrated good safety and anti-tumor effects in preclinical studies. Currently, regulating genes related to viral particle spread [115] (US3, UL24, etc.) is also receiving considerable attention. Editing these genes aims to optimize HSV spread within tumor tissues while reducing damage to normal tissues.

3.2. Clinical Advances

T-VEC’s FDA approval for melanoma and G47Δ’s efficacy in glioblastoma highlight oHSV’s clinical potential, though delivery challenges persist. HSV investigational drugs with different genetic modifications have shown good broad-spectrum anti-tumor effects in preclinical models and are being actively pursued for clinical application. Safety, drug resistance, dosage, and administration route are important factors affecting clinical translation. Currently, clinical studies are underway for various tumors, such as malignant brain tumors, skin or subcutaneous malignant tumors, head and neck cancer, lung cancer, liver cancer, pancreatic cancer, and colorectal cancer.

3.2.1. Malignant Brain Tumors

Glioblastoma, as the most malignant brain tumor [119], is extremely difficult to treat. Among current oncolytic virus therapies (Table 8), G207 has the ICP34.5 gene knocked out to reduce neurotoxicity [120], and G47Δ further deletes the ICP47 gene on this basis to improve viral infection efficiency [27]. Phase I (UMIN000002661) and Phase II (UMIN000015995) clinical studies showed that G47Δ treatment in patients with recurrent glioblastoma resulted in a median survival of 7.3 months, with a one-year survival rate of 38.5% [121,122] and rQNestin34.5v.2 extending overall survival. Other viruses under investigation include rQNestin34.5v.2 [123,124], regulated by the Nestin-1 (Nestin-1) promoter; HSV1716 [125], with ICP34.5 gene deletion; and C134 [126,127], with double-copy ICP34.5 gene deletion and insertion of the Human Cytomegalovirus-TRS1 gene. Clinical data show good safety with intratumoral administration, effective viral replication, and no long-term adverse reactions.
Combination therapy strategies have shown further optimization of efficacy. G207 combined with a single 5Gy radiotherapy (NCT02457845) can increase viral replication and intratumoral spread, enhancing the anti-tumor immune effect [128]. The same regimen is being applied to pediatric malignant gliomas to assess efficacy and safety (NCT04482933). M032, with IL-12 gene knock-in, showed in a Phase I clinical study (NCT02062827) that it could induce increased expression of Interferon-γ (Interferon-γ, IFN-γ) and had a certain therapeutic effect on recurrent malignant glioma [129,130]. Its synergistic mechanism with pembrolizumab is being explored (NCT05084430). These advances highlight the potential of oncolytic viruses in multi-modal combination strategies to improve GBM outcomes.

3.2.2. Skin and Soft Tissue Sarcomas

In clinical studies targeting cutaneous melanoma (Table 9), T-VEC, developed by Amgen, has shown significant efficacy [131]. This investigational drug reduces neurotoxicity by knocking out the ICP34.5 gene of HSV-1 and enhances antigen presentation by knocking out the ICP47 gene while also inserting the GM-CSF gene to boost anti-tumor immune response [132,133,134]. Results from a Phase III clinical trial (NCT00769704) showed that T-VEC monotherapy for advanced melanoma achieved an objective response rate (ORR) of 26%, with a significantly prolonged median survival compared to the control group [135,136]. Notably, 64% of patients experienced regression of distant lesions, suggesting T-VEC can induce systemic anti-tumor immunity [137]. Another clinical study combining T-VEC with ipilimumab (NCT01740297) showed a significantly higher ORR than monotherapy, with disease remission in visceral metastatic sites, indicating a synergistic effect between T-VEC and immune checkpoint inhibitors. [138]. The combination of T-VEC and ipilimumab marks a trend toward synergistic approaches. T-VEC has also demonstrated good therapeutic effects on non-melanoma skin cancers. In 2022, a clinical study (NCT03458117) was initiated to evaluate the efficacy, safety, and tolerability of repeated T-VEC injections in patients with non-melanoma skin cancer. Some reports indicated chronic granulomatous dermatitis at the T-VEC injection site [139], but the nodules spontaneously resolved after stopping injections and did not easily recur [139].
OH2 is one of the few oncolytic virus investigational drugs based on HSV-2. It has the human GM-CSF gene inserted into its genome and has shown durable anti-tumor activity in melanoma and soft tissue sarcoma [140,141], especially for patients who have progressed on anti-PD-1 therapy. Due to the limitations of intratumoral administration, more oHSV investigational drugs are currently in clinical research for skin and other superficial malignant tumors.

3.2.3. Mucosal Epithelial Tumors

Clinical studies indicate that oncolytic HSV has broad-spectrum anti-tumor effects, achieving encouraging results in various mucosal epithelial malignancies such as head and neck cancer, lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, and bladder cancer (Table 10). For example, T-VEC not only exhibits good anti-tumor activity against melanoma, but further studies have found it also has certain therapeutic effects on diseases like head and neck cancer [140], liver cancer [142], and pancreatic cancer [143], enhancing immune-related activity in the body, prolonging patient survival with good safety [144]. Exploration of T-VEC for more indications is ongoing. The efficacy of OH2 monotherapy or in combination with other therapies has been validated in multiple preclinical tumor models [48,49,50,51]. Safety evaluations indicate OH2 is safe and suitable for clinical research [48]. Several clinical studies (NCT03866525, NCT04637698, NCT05232136, and NCT05248789) show that OH2 has broad application prospects in advanced refractory head and neck cancer, gastric cancer, pancreatic cancer, bladder cancer, and other diseases, enhancing the body’s adaptive immune response capability [145] and exhibiting synergistic anti-tumor effects when combined with ICIs [140]. Furthermore, various administration routes have been developed based on the different locations, stages, and progression characteristics of tumors, including intratumoral injection (most common), intravenous injection (NCT05598268, NCT06283303, NCT06200363), nebulization inhalation (NCT06228326), and bladder instillation (NCT06427291, NCT05232136). This demonstrates the characteristics of oncolytic virus therapy, including broad indications and diverse administration routes. While oHSV has shown promise in clinical trials, challenges in delivery and administration limit its efficacy, prompting innovative strategies discussed next.

4. Technical Challenges and Solutions

4.1. Targeted Delivery

Optimizing the targeting of oncolytic virus therapy has always been central to improving efficacy and safety. Genetic engineering techniques to modify the viral genome can enhance tumor targeting. Key viral genes can be deleted to make replication dependent on tumor-specific pathways. The most common modification is the deletion of the ICP34.5 gene. The viral ICP34.5 protein promotes viral replication by inhibiting the protein kinase R (PKR) and eukaryotic Initiation Factor-2 (eIF2) signaling pathways in normal cells. Knocking out the ICP34.5 gene in HSV blocks its replication in normal cells [146]. In contrast, tumor cells often have an abnormal PKR-eIF2 pathway, allowing HSV lacking the ICP34.5 gene to proliferate only within tumor cells [147], indirectly improving the virus’s tumor cell targeting. Furthermore, surface modification of HSV also affects its targeting. In 2020, Ye et al. [148] covalently modified the HSV drug G207 with a Folate-Poly Ethylene Glycol (FA-PEG) conjugate. This significantly enhanced the targeting of G207 to tumor cells with high folate receptor expression while reducing immunogenicity, demonstrating potential therapeutic value.
To overcome systemic barriers and enhance tumor-specific accumulation, various carriers are being explored. NPs have characteristics such as small size, large surface area, and the ability to cross cellular or tissue barriers [149,150]. They can protect viruses from neutralization and achieve precise delivery [151,152], gradually becoming emerging tools in the biomedical field. In 2024, Totsch et al. [6] studied the pharmacodynamic effects of G207 combined with a self-assembling nanoparticle vaccine (co-delivering antigen peptides and a toll-like receptor 7/8 agonist, called SNAPvax) on the TC-1 model. They found that the combination therapy enhanced the oncolytic effect and induced a more durable T cell immune response. In 2022, Howard et al. [153] combined HSV1716 with nanomagnetic particles (Magnetosomes, MAG) isolated from magnetotactic bacteria. With the aid of an external magnetic field, this approach “navigates” the oncolytic virus, achieving specific tumor targeting while protecting HSV1716 from antibody neutralization. NP biodegradation products can accumulate in cells, potentially causing mutations [154], limiting their role in drug delivery. Therefore, research on the safety and scalability of NPs needs to be strengthened [155] to promote their development in the field of drug therapy.
Biological carriers also show advantages in the targeted delivery of oncolytic viruses. Mesenchymal stem cells (MSCs), as new carriers for targeting tumors and enhancing viral efficacy, are being investigated [156,157,158]. MSCs have been found to migrate to tumor sites via chemotaxis [159,160], possess anti-inflammatory and immunosuppressive properties [161], and induce an immune-tolerant state in the body. This allows loaded oncolytic viruses to evade host immune surveillance and be precisely delivered to tumor tissues [162,163], potentially overcoming the obstacle of local administration only [164]. In 2015, Leoni et al. [165] infected MSCs with HER2-targeted oHSV. Intravenous injection into mice with ovarian cancer lung metastases and breast cancer brain metastases significantly reduced tumor metastasis. Biodistribution assessment showed successful penetration of the BBB, with minimal distribution in normal tissues [164], and activity was maintained after multiple passages [166]. In 2014, Duebgen et al. [167] injected oHSV into hMSCs and found that they could effectively produce progeny oHSV, significantly extending the average lifespan of glioblastoma mice. In 2017, Du et al. [168] studied the therapeutic effect of internal carotid artery (ICA) delivery of MSC-oHSV on brain metastatic melanoma. Fluorescence imaging showed that MSC-oHSV had superior tumor-tracking ability compared to oHSV alone, resulting in a stronger anti-tumor effect. In 2020, Mahasa et al. [169] further confirmed through mathematical modeling that MSC-mediated viral delivery offers better safety and targeting while also demonstrating a synergistic anti-tumor effect. Overall, MSCs have broad application prospects as universal carriers for oncolytic viruses. MSC-based oncolytic virus therapy may also be widely applicable to metastatic lesions in organs such as the liver, colon, and lungs, providing a treatment strategy for metastatic cancer. It also holds promise for overcoming the obstacles of systemic delivery of oncolytic viruses, but issues such as long-term safety [170] and excessive immunosuppression [171] still require systematic research.

4.2. Administration Routes

The administration route is key to the effective accumulation of oncolytic viruses at the tumor site and their therapeutic efficacy. Currently, administration routes for oncolytic viruses include systemic administration (intravenous injection) and local administration (intratumoral injection) [172]. Intravenous injection has clear advantages for metastatic tumors, reaching lesions via systemic blood circulation. However, it faces numerous challenges in clinical application: ① Oncolytic viruses entering the bloodstream can be neutralized by pre-existing antiviral antibodies in the serum, leading to direct viral clearance. ② Blood circulates throughout the body, and viral membrane receptors are widely present, making it easy for viruses to infect non-tumor cells, potentially causing damage to normal tissues. ③ Blood can dilute the virus investigational drug, preventing it from enriching at the tumor site and affecting its biodistribution [173]. ④ When tumor lesions are widely distributed and intratumoral blood vessels are abnormally branched and tortuous, the drug can hardly reach every metastatic lesion uniformly [174], affecting treatment efficacy. Therefore, based on the anti-tumor mechanisms of oncolytic viruses and the characteristics of the viruses themselves, most clinical studies of oncolytic virus therapy currently use intratumoral injection. Intratumoral injection allows the drug to directly reach the tumor lesion, which is beneficial for the efficacy and safety of oncolytic virus therapy. However, intratumoral injection may lead to uneven drug distribution within the tumor. Solid tumors have a dense extracellular matrix (ECM) [175], and high permeability of intratumoral blood vessels can lead to high intratumoral pressure [176], hindering viral infiltration. The presence of ECM can impede the spread of oncolytic viruses. Some strategies have been developed, such as pretreatment with enzymes (collagenase or hyaluronidase) or relaxin [177], to promote viral diffusion within tumor tissue. Alternatively, genetic engineering can be used to introduce genes encoding ECM-degrading enzymes into the oncolytic virus genome [178], enabling them to express these enzymes and increase the spread of oncolytic viruses in tumor tissue. Currently, all marketed oncolytic virus drugs are administered intratumorally. Although this allows for precise concentration control at the tumor site, this method is more suitable for superficial tumors, such as melanoma. For metastatic and non-superficial tumors, clinical needs are not yet met. Moreover, the risks associated with intratumoral administration procedures can make repeated dosing difficult [179], causing considerable distress to patients. More convenient administration methods that reduce patient suffering should be investigated to avoid problems associated with the delivery route and mitigate adverse reactions. Developing special administration methods based on tumor characteristics (e.g., nanocarrier delivery [180,181], ultrasound-guided delivery [182]) requires further exploration in future research.

4.3. Quality Control

Oncolytic virus products are susceptible to contamination, making the detection of adventitious viruses crucial. Since oncolytic virus products are themselves “live viruses,” distinguishing between the oncolytic virus and adventitious viruses using traditional detection methods like culture-based assays presents significant difficulties. If neutralizing antibodies are used, it is challenging to select antibodies that can effectively neutralize the oncolytic virus. Furthermore, the extensive use of neutralizing antibodies can dilute the test sample, potentially leading to false-negative results. These factors pose challenges to detection methods. oHSV products require stringent quality control to ensure safety and consistency. To better reduce the risk of adventitious virus contamination in oncolytic virus products, strategies can be developed from multiple aspects to ensure quality control, such as purity, potency, and safety testing to ensure the use of appropriate strains [183]. Firstly, cell banks, virus seed lots, and other source materials can all introduce adventitious viruses. Therefore, testing for adventitious viruses is required before using these materials, combined with risk assessment based on their origin, passage history, and raw materials used during bank preparation. For example, T-VEC, which is approved by the FDA, is essentially a live, lytic HSV-1 virus. When samples containing T-VEC are added to indicator cell lines (such as Vero cells) by traditional foreign virus detection methods, the T-VEC self-infection replicates efficiently, resulting in significant cytopathic effect (CPE). This strong effect can “mask” possible low-level exogenous virus contamination, making it impossible to interpret test results and posing a serious product safety and regulatory risk. Comprehensive screening of cell banks and virus seed lots is performed using sensitive methods like polymerase chain reaction (PCR) and gene sequencing to rule out the risk of specific adventitious agent contamination at the source. Secondly, a workaround has been used to develop a high-titer neutralizing antibody specific for oHSV products. It is expected to “neutralize” the foreign virus in the oHSV product so that foreign viral contaminants that are not easily recognized by antibodies are detected in the indicator cells. However, this method has the problem of high development cost, and its validity and reliability need to be considered. To improve the purity and potency of oHSV products, manufacturing processes include robust purification steps like nuclease treatment, ultracentrifugation, and dialysis to remove contaminants [184]. The final product’s infectious potency is quantified using validated methods like plaque assays to ensure consistent dosing [185,186]. Finally, samples are traditionally inoculated into animals such as newborn mice or chicken embryos to test the safety of oHSV products. However, this approach has been widely recognized as scientifically unreliable and unethical. The genetic identity of the oHSV product is confirmed via sequencing to ensure all intended modifications are present and no unintended mutations have occurred.
For an innovative product such as oHSV, the safety testing strategy must not only be scientific and accurate, including uncontrolled viral replication, off-target toxicity, and genetic instability, but also comply with the regulatory requirements of major regulatory agencies around the world [187]. The FDA, which classifies oncolytic viruses as gene therapy or microbial vector products [188], imposes requirements for chemistry, manufacturing, and control through a series of guidelines. Comprehensive characterization of cell banks and virus seeds, strict control of raw materials for production, and comprehensive detection of exogenous agents are emphasized. The European Medicines Agency (EMA) regulates oncolytic viral products through its series of guidelines for advanced therapy medicinal products (ATMPs) [189]. The adoption of a risk-based approach to development and evaluation is emphasized, while covering multiple aspects of quality, nonclinical, and clinical development [190]. The National Medical Products Administration (NMPA) has also issued technical guidelines for oncolytic virus products. Quality risks related to production materials, genetic stability of the virus, and contamination by exogenous factors were clearly pointed out. Enterprises are required to take comprehensive risk control measures to ensure product safety.

5. Conclusions and Future Directions

5.1. Conclusions

Oncolytic viruses show promising application prospects in tumor therapy, but several technical challenges remain to be addressed. These include issues such as targeting (a key problem in cancer therapy is improving tumor targeting), vector selection (improving viral infection efficiency), and antibody neutralization (viruses entering the body trigger an immune response, producing antibodies that neutralize the virus and reduce efficacy).
Viral vectors carry an inherent risk of pathogenicity, and safety remains the most concerning issue during clinical translation. Although oncolytic viruses are designed to be selective, factors such as non-stringent targeting mechanisms, the influence of the host immune system, or abnormal viral behavior can lead to viruses not accurately infecting tumor cells, resulting in “off-target effects” manifested as local inflammation, tissue damage, and other adverse reactions [191]. In some cases, oncolytic viruses can enter the bloodstream and spread systemically, potentially affecting “distant” tissues and organs; being non-specifically taken up by the lungs, liver, or spleen [192]; and triggering inflammation in non-cancerous sites or autoimmune disease-like reactions [12]. Viral particles in the blood can also activate the complement system, initiating a cascade of protease reactions that lead to the deposition of the membrane attack complex (MAC) [193], causing lysis and destruction of normal cells and a series of adverse reactions. Concurrently, the entry of viruses into the body induces varying degrees of host antiviral immune responses. Currently, this problem cannot be completely resolved at the viral level. Existing approaches often involve combination therapies, suppression of the host immune system, or enhancement of the virus’s ability to induce an anti-tumor response, striving for a balance between antiviral and anti-tumor responses.
Oncolytic viruses are engineered to replicate specifically in tumor cells, lyse them, and release tumor-associated antigens (TAAs), stimulating an adaptive immune response. However, pre-existing immunity to the viral vector and the subsequent production of neutralizing antibodies can affect the intensity and efficiency of the adaptive immune response generated by the body [194]. Therefore, the impact of viral immunogenicity on therapeutic efficacy needs careful consideration. Viral modification processes usually involve the modification or deletion of virulence genes, such as ICP0, ICP34.5, and UL39. The deletion of such genes may affect the immunogenicity of the virus and reduce its replication and spread in tumor cells. Furthermore, HSV therapy typically prioritizes intratumoral injection, and physical barriers like the ECM can limit the biodistribution and spread of the drug [195]. Therefore, combining oncolytic virus therapy with other therapies is crucial, allowing for flexible selection of treatment plans based on the different characteristics of the patient’s tumor and leveraging the respective advantages of different therapies.
The emergence of new technologies is actively promoting oncolytic virus therapy. For instance, nanotechnology offers significant advantages in discovering potential therapeutic targets and predicting biomarkers. Utilizing patient-derived 3D organoids to screen oncolytic virus investigational drugs, employing multi-omics analysis of the tumor microenvironment, and developing oncolytic virus platforms with stronger tumor specificity and higher replication efficiency will facilitate the personalized development of oncolytic virus therapy. The integration of artificial intelligence (AI) algorithms for virus design, prediction of efficacy, and formulation of personalized treatment plans will also be an important direction for HSV therapy. Compared to other viruses, HSV has distinct advantages. Its ability to cross the blood–brain barrier has yet to be further exploited by researchers. It can carry larger exogenous genes than other viral vectors, offering tremendous manipulability. Further advancements in gene-editing technologies like CRISPR/Cas9 will provide more powerful tools for the precise and efficient modification of HSV [64,196,197], holding unparalleled advantages for treating neurological diseases and cancer.

5.2. Future Directions

Future core research questions for oHSV will focus on utilizing a new generation of oHSV that can improve tumor heterogeneity and immunosuppressive microenvironment, enhance oncolytic effect, and minimize neurotoxicity. For example, CRISPR/Cas9 and other precision gene-editing tools can be used to create next-generation oHSV. This could involve knocking in/knocking out multiple transgenes, incorporating safety switches, or editing viral glycoproteins to evade neutralizing antibodies. Biomarkers should be identified and validated (e.g., tumor expression of nectin-1, PD-L1 status, or host interferon signature) to select patients most likely to have a response to oHSV therapy, enabling a more personalized approach. Synergistic therapies beyond checkpoint inhibitors, including with CAR-T cell therapy, targeted small molecule inhibitors, and radiotherapy, can overcome drug resistance and enhance efficacy. Artificial intelligence learning algorithms can be employed to design novel virus backbones, predict therapeutic efficacy, and formulate personalized treatment regimens based on patient-specific tumor data.

Author Contributions

Y.Z. (Yiyang Zheng) was responsible for the manuscript writing and data collection. Y.P. and Q.H. were responsible for funding acquisition and conceptualization. C.D., J.L., T.C., Y.Z. (Yuan Zhang), D.T. and J.W. made significant contributions to the conception of the article and data analysis. C.D., J.L., T.C., Y.Z. (Yuan Zhang), D.T. and J.W. checked and revised the article. All authors have read and agreed to the published version of the manuscript.

Funding

This review was supported by the State Key Laboratory of Drug Regulatory Sciences (standardized construction and application of tumor organoids, 2025SKLDRS0347; research on key technologies and methods for evaluating the nonclinical efficacy of polylactic acid macroporous microsphere long-acting vaccines, 2025SKLDRS0351).

Conflicts of Interest

The authors have no conflicts of interest to declare.

References

  1. Hoster, H.A.; Zanes, R.P., Jr.; Von Haam, E. Studies in Hodgkin’s Syndrome; the Association of Viral Hepatitis and Hodgkin’s Disease; a Preliminary Report. Cancer Res. 1949, 9, 473–480. [Google Scholar]
  2. Moore, A.E. The Destructive Effect of the Virus of Russian Far East Encephalitis on the Transplantable Mouse Sarcoma 180. Cancer 1949, 2, 525–534. [Google Scholar] [CrossRef]
  3. Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. Experimental Therapy of Human Glioma by Means of a Genetically Engineered Virus Mutant. Science 1991, 252, 854–856. [Google Scholar] [CrossRef]
  4. Ledford, H. Cancer-Fighting Viruses Win Approval. Nature 2015, 526, 622–623. [Google Scholar] [CrossRef] [PubMed]
  5. Zeng, J.; Li, X.; Sander, M.; Zhang, H.; Yan, G.; Lin, Y. Oncolytic Viro-Immunotherapy: An Emerging Option in the Treatment of Gliomas. Front. Immunol. 2021, 12, 721830. [Google Scholar] [CrossRef] [PubMed]
  6. Totsch, S.K.; Ishizuka, A.S.; Kang, K.D.; Gary, S.E.; Rocco, A.; Fan, A.E.; Zhou, L.; Valdes, P.A.; Lee, S.; Li, J.; et al. Combination Immunotherapy with Vaccine and Oncolytic Hsv Virotherapy Is Time Dependent. Mol. Cancer Ther. 2024, 23, 1273–1281. [Google Scholar] [CrossRef]
  7. Young, C.C.; Narsinh, K.H.; Chen, S.R.; Ansari, S.A.; Hetts, S.W.; Lang, F.F.; Wintermark, M.; Kan, P.T. State of Practice: A Report from the Inaugural Snis Neurointerventional Oncology Summit. AJNR Am. J. Neuroradiol. 2025, ajnr.A8902. [Google Scholar] [CrossRef]
  8. Wei, D.; Xu, J.; Liu, X.Y.; Chen, Z.N.; Bian, H. Fighting Cancer with Viruses: Oncolytic Virus Therapy in China. Hum. Gene Ther. 2018, 29, 151–159. [Google Scholar] [CrossRef]
  9. Xia, Z.J.; Chang, J.H.; Zhang, L.; Jiang, W.Q.; Guan, Z.Z.; Liu, J.W.; Zhang, Y.; Hu, X.H.; Wu, G.H.; Wang, H.Q.; et al. Phase Iii Randomized Clinical Trial of Intratumoral Injection of E1b Gene-Deleted Adenovirus (H101) Combined with Cisplatin-Based Chemotherapy in Treating Squamous Cell Cancer of Head and Neck or Esophagus. Ai Zheng 2004, 23, 1666–1670. [Google Scholar] [PubMed]
  10. Lee, A. Nadofaragene Firadenovec: First Approval. Drugs 2023, 83, 353–357. [Google Scholar] [CrossRef]
  11. Su, Y.; Su, C.; Qin, L. Current Landscape and Perspective of Oncolytic Viruses and Their Combination Therapies. Transl. Oncol. 2022, 25, 101530. [Google Scholar] [CrossRef]
  12. Lawler, S.E.; Speranza, M.C.; Cho, C.F.; Chiocca, E.A. Oncolytic Viruses in Cancer Treatment: A Review. JAMA Oncol. 2017, 3, 841–849. [Google Scholar] [CrossRef]
  13. Bronger, H.; Singer, J.; Windmüller, C.; Reuning, U.; Zech, D.; Delbridge, C.; Dorn, J.; Kiechle, M.; Schmalfeldt, B.; Schmitt, M.; et al. Cxcl9 and Cxcl10 Predict Survival and Are Regulated by Cyclooxygenase Inhibition in Advanced Serous Ovarian Cancer. Br. J. Cancer 2016, 115, 553–563. [Google Scholar] [CrossRef]
  14. Muscolini, M.; Tassone, E.; Hiscott, J. Oncolytic Immunotherapy: Can’t Start a Fire without a Spark. Cytokine Growth Factor Rev. 2020, 56, 94–101. [Google Scholar] [CrossRef]
  15. Kaufman, H.L.; Kohlhapp, F.J.; Zloza, A. Oncolytic Viruses: A New Class of Immunotherapy Drugs. Nat. Rev. Drug Discov. 2015, 14, 642–662. [Google Scholar] [CrossRef]
  16. Tsuji, T.; Nakamori, M.; Iwahashi, M.; Nakamura, M.; Ojima, T.; Iida, T.; Katsuda, M.; Hayata, K.; Ino, Y.; Todo, T.; et al. An Armed Oncolytic Herpes Simplex Virus Expressing Thrombospondin-1 Has an Enhanced in Vivo Antitumor Effect against Human Gastric Cancer. Int. J. Cancer 2013, 132, 485–494. [Google Scholar] [CrossRef]
  17. Zhang, W.; Fulci, G.; Wakimoto, H.; Cheema, T.A.; Buhrman, J.S.; Jeyaretna, D.S.; Stemmer Rachamimov, A.O.; Rabkin, S.D.; Martuza, R.L. Combination of Oncolytic Herpes Simplex Viruses Armed with Angiostatin and Il-12 Enhances Antitumor Efficacy in Human Glioblastoma Models. Neoplasia 2013, 15, 591–599. [Google Scholar] [CrossRef]
  18. Zhang, G.; Jin, G.; Nie, X.; Mi, R.; Zhu, G.; Jia, W.; Liu, F. Enhanced Antitumor Efficacy of an Oncolytic Herpes Simplex Virus Expressing an Endostatin-Angiostatin Fusion Gene in Human Glioblastoma Stem Cell Xenografts. PLoS ONE 2014, 9, e95872. [Google Scholar] [CrossRef]
  19. Goodwin, J.M.; Schmitt, A.D.; McGinn, C.M.; Fuchs, B.C.; Kuruppu, D.; Tanabe, K.K.; Lanuti, M. Angiogenesis Inhibition Using an Oncolytic Herpes Simplex Virus Expressing Endostatin in a Murine Lung Cancer Model. Cancer Investig. 2012, 30, 243–250. [Google Scholar] [CrossRef]
  20. Breitbach, C.J.; Bell, J.C.; Hwang, T.H.; Kirn, D.H.; Burke, J. The Emerging Therapeutic Potential of the Oncolytic Immunotherapeutic Pexa-Vec (Jx-594). Oncolytic Virother. 2015, 4, 25–31. [Google Scholar] [CrossRef]
  21. Omarova, S.; Cannon, A.; Weiss, W.; Bruccoleri, A.; Puccio, J. Genital Herpes Simplex Virus-an Updated Review. Adv. Pediatr. 2022, 69, 149–162. [Google Scholar] [CrossRef]
  22. Ahmad, I.; Wilson, D.W. Hsv-1 Cytoplasmic Envelopment and Egress. Int. J. Mol. Sci. 2020, 21, 5969. [Google Scholar] [CrossRef]
  23. Roizman, B.; Whitley, R.J. An Inquiry into the Molecular Basis of Hsv Latency and Reactivation. Annu. Rev. Microbiol. 2013, 67, 355–374. [Google Scholar] [CrossRef]
  24. Corey, L.; Wald, A. Maternal and Neonatal Herpes Simplex Virus Infections. N. Engl. J. Med. 2009, 361, 1376–1385. [Google Scholar] [CrossRef]
  25. Bailer, S.M.; Funk, C.; Riedl, A.; Ruzsics, Z. Herpesviral Vectors and Their Application in Oncolytic Therapy, Vaccination, and Gene Transfer. Virus Genes 2017, 53, 741–748. [Google Scholar] [CrossRef]
  26. Chiu, M.; Armstrong, E.J.L.; Jennings, V.; Foo, S.; Crespo-Rodriguez, E.; Bozhanova, G.; Patin, E.C.; McLaughlin, M.; Mansfield, D.; Baker, G.; et al. Combination Therapy with Oncolytic Viruses and Immune Checkpoint Inhibitors. Expert Opin. Biol. Ther. 2020, 20, 635–652. [Google Scholar] [CrossRef]
  27. Ma, W.; He, H.; Wang, H. Oncolytic Herpes Simplex Virus and Immunotherapy. BMC Immunol. 2018, 19, 40. [Google Scholar] [CrossRef]
  28. Huang, Y.; Song, Y.; Li, J.; Lv, C.; Chen, Z.S.; Liu, Z. Receptors and Ligands for Herpes Simplex Viruses: Novel Insights for Drug Targeting. Drug Discov. Today 2022, 27, 185–195. [Google Scholar] [CrossRef]
  29. Hensen, L.C.M.; Hoeben, R.C.; Bots, S.T.F. Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy. Int. J. Mol. Sci. 2020, 21, 6828. [Google Scholar] [CrossRef]
  30. Wu, D.; Lou, Y.C.; Chang, W.; Tzou, D.M. Nmr Assignments of Vaccinia Virus Protein A28: An Entry-Fusion Complex Component. Biomol. NMR Assign. 2021, 15, 117–120. [Google Scholar] [CrossRef]
  31. Danthi, P.; Holm, G.H.; Stehle, T.; Dermody, T.S. Reovirus Receptors, Cell Entry, and Proapoptotic Signaling. Adv. Exp. Med. Biol. 2013, 790, 42–71. [Google Scholar]
  32. Blechacz, B.; Russell, S.J. Parvovirus Vectors: Use and Optimisation in Cancer Gene Therapy. Expert Rev. Mol. Med. 2004, 6, 1–24. [Google Scholar] [CrossRef]
  33. Inal, J.M.; Jorfi, S. Coxsackievirus B Transmission and Possible New Roles for Extracellular Vesicles. Biochem. Soc. Trans. 2013, 41, 299–302. [Google Scholar] [CrossRef]
  34. Selinka, H.C.; Wolde, A.; Sauter, M.; Kandolf, R.; Klingel, K. Virus-Receptor Interactions of Coxsackie B Viruses and Their Putative Influence on Cardiotropism. Med. Microbiol. Immunol. 2004, 193, 127–131. [Google Scholar] [CrossRef]
  35. Burke, M.J. Oncolytic Seneca Valley Virus: Past Perspectives and Future Directions. Oncolytic Virother. 2016, 5, 81–89. [Google Scholar] [CrossRef]
  36. Corbett, V.; Hallenbeck, P.; Rychahou, P.; Chauhan, A. Evolving Role of Seneca Valley Virus and Its Biomarker Tem8/Antxr1 in Cancer Therapeutics. Front. Mol. Biosci. 2022, 9, 930207. [Google Scholar] [CrossRef]
  37. Buijs, P.R.; Verhagen, J.H.; van Eijck, C.H.; van den Hoogen, B.G. Oncolytic Viruses: From Bench to Bedside with a Focus on Safety. Hum. Vaccin. Immunother. 2015, 11, 1573–1584. [Google Scholar] [CrossRef]
  38. Bhattacharjee, S.; Yadava, P.K. Measles Virus: Background and Oncolytic Virotherapy. Biochem. Biophys. Rep. 2018, 13, 58–62. [Google Scholar] [CrossRef]
  39. Saga, K.; Kaneda, Y. Oncolytic Sendai Virus-Based Virotherapy for Cancer: Recent Advances. Oncolytic Virother. 2015, 4, 141–147. [Google Scholar]
  40. Huang, F.; Dai, C.; Zhang, Y.; Zhao, Y.; Wang, Y.; Ru, G. Development of Molecular Mechanisms and Their Application on Oncolytic Newcastle Disease Virus in Cancer Therapy. Front. Mol. Biosci. 2022, 9, 889403. [Google Scholar] [CrossRef]
  41. Ammayappan, A.; Peng, K.W.; Russell, S.J. Characteristics of Oncolytic Vesicular Stomatitis Virus Displaying Tumor-Targeting Ligands. J. Virol. 2013, 87, 13543–13555. [Google Scholar] [CrossRef]
  42. Dinarello, C.A. Historical Insights into Cytokines. Eur. J. Immunol. 2007, 37 (Suppl. S1), S34–S45. [Google Scholar] [CrossRef]
  43. Estrada, J.; Zhan, J.; Mitchell, P.; Werner, J.; Beltran, P.J.; DeVoss, J.; Qing, J.; Cooke, K.S. Oncovex(Mgm-Csf)Expands Tumor Antigen-Specific Cd8+ T-Cell Response in Preclinical Models. J. Immunother Cancer 2023, 11, e006374. [Google Scholar] [CrossRef]
  44. Hu, H.; Zhang, S.; Cai, L.; Duan, H.; Li, Y.; Yang, J.; Wang, Y.; Liu, B.; Dong, S.; Fang, Z.; et al. A Novel Cocktail Therapy Based on Quintuplet Combination of Oncolytic Herpes Simplex Virus-2 Vectors Armed with Interleukin-12, Interleukin-15, Gm-Csf, Pd1v, and Il-7 × Ccl19 Results in Enhanced Antitumor Efficacy. Virol. J. 2022, 19, 74. [Google Scholar] [CrossRef] [PubMed]
  45. Kim, K.J.; Moon, D.; Kong, S.J.; Lee, Y.S.; Yoo, Y.; Kim, S.; Kim, C.; Chon, H.J.; Kim, J.H.; Choi, K.J. Antitumor Effects of Il-12 and Gm-Csf Co-Expressed in an Engineered Oncolytic Hsv-1. Gene Ther. 2021, 28, 186–198. [Google Scholar] [CrossRef]
  46. De Lucia, M.; Cotugno, G.; Bignone, V.; Garzia, I.; Nocchi, L.; Langone, F.; Petrovic, B.; Sasso, E.; Pepe, S.; Froechlich, G.; et al. Retargeted and Multi-Cytokine-Armed Herpes Virus Is a Potent Cancer Endovaccine for Local and Systemic Anti-Tumor Treatment. Mol. Ther. Oncolytics 2020, 19, 253–264. [Google Scholar] [CrossRef]
  47. Crespo-Rodriguez, E.; Bergerhoff, K.; Bozhanova, G.; Foo, S.; Patin, E.C.; Whittock, H.; Buus, R.; Haider, S.; Muirhead, G.; Thway, K.; et al. Combining Braf Inhibition with Oncolytic Herpes Simplex Virus Enhances the Immune-Mediated Antitumor Therapy of Braf-Mutant Thyroid Cancer. J. Immunother Cancer 2020, 8, e000698. [Google Scholar] [CrossRef] [PubMed]
  48. Wang, Y.; Zhou, X.; Wu, Z.; Hu, H.; Jin, J.; Hu, Y.; Dong, Y.; Zou, J.; Mao, Z.; Shi, X.; et al. Preclinical Safety Evaluation of Oncolytic Herpes Simplex Virus Type 2. Hum. Gene Ther. 2019, 30, 651–660. [Google Scholar] [CrossRef]
  49. Kong, D.; Yang, Z.; Li, G.; Wu, Q.; Gu, Z.; Wan, D.; Zhang, Q.; Zhang, X.; Cheng, S.; Liu, B.; et al. Sirpα Antibody Combined with Oncolytic Virus Oh2 Protects against Tumours by Activating Innate Immunity and Reprogramming the Tumour Immune Microenvironment. BMC Med. 2022, 20, 376. [Google Scholar] [CrossRef]
  50. Zheng, Y.; Wang, X.; Ji, Q.; Fang, A.; Song, L.; Xu, X.; Lin, Y.; Peng, Y.; Yu, J.; Xie, L.; et al. Oh2 Oncolytic Virus: A Novel Approach to Glioblastoma Intervention through Direct Targeting of Tumor Cells and Augmentation of Anti-Tumor Immune Responses. Cancer Lett. 2024, 589, 216834. [Google Scholar] [CrossRef] [PubMed]
  51. Dong, S.; Liu, B.; Hu, S.; Guo, F.; Zhong, Y.; Cai, Q.; Zhang, S.; Qian, Y.; Wang, J.; Zhou, F. A Novel Oncolytic Virus Induces a Regional Cytokine Storm and Safely Eliminates Malignant Ascites of Colon Cancer. Cancer Med. 2022, 11, 4297–4309. [Google Scholar] [CrossRef]
  52. Alessandrini, F.; Menotti, L.; Avitabile, E.; Appolloni, I.; Ceresa, D.; Marubbi, D.; Campadelli-Fiume, G.; Malatesta, P. Eradication of Glioblastoma by Immuno-Virotherapy with a Retargeted Oncolytic Hsv in a Preclinical Model. Oncogene 2019, 38, 4467–4479. [Google Scholar] [CrossRef]
  53. Leoni, V.; Vannini, A.; Gatta, V.; Rambaldi, J.; Sanapo, M.; Barboni, C.; Zaghini, A.; Nanni, P.; Lollini, P.L.; Casiraghi, C.; et al. A Fully-Virulent Retargeted Oncolytic Hsv Armed with Il-12 Elicits Local Immunity and Vaccine Therapy Towards Distant Tumors. PLoS Pathog. 2018, 14, e1007209. [Google Scholar] [CrossRef]
  54. Friedman, G.K.; Bernstock, J.D.; Chen, D.; Nan, L.; Moore, B.P.; Kelly, V.M.; Youngblood, S.L.; Langford, C.P.; Han, X.; Ring, E.K.; et al. Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic Hsv-1 Virotherapy Correlates with Nectin-1 Expression. Sci. Rep. 2018, 8, 13930. [Google Scholar] [CrossRef]
  55. Ring, E.K.; Li, R.; Moore, B.P.; Nan, L.; Kelly, V.M.; Han, X.; Beierle, E.A.; Markert, J.M.; Leavenworth, J.W.; Gillespie, G.Y.; et al. Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic Hsv-1 M002. Mol. Ther. Oncolytics 2017, 7, 27–36. [Google Scholar] [CrossRef] [PubMed]
  56. Megison, M.L.; Gillory, L.A.; Stewart, J.E.; Nabers, H.C.; Mroczek-Musulman, E.; Waters, A.M.; Coleman, J.M.; Kelly, V.; Markert, J.M.; Gillespie, G.Y.; et al. Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors. PLoS ONE 2014, 9, e86843. [Google Scholar] [CrossRef]
  57. Gillory, L.A.; Megison, M.L.; Stewart, J.E.; Mroczek-Musulman, E.; Nabers, H.C.; Waters, A.M.; Kelly, V.; Coleman, J.M.; Markert, J.M.; Gillespie, G.Y.; et al. Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Neuroblastoma. PLoS ONE 2013, 8, e77753. [Google Scholar] [CrossRef] [PubMed]
  58. Chouljenko, D.V.; Murad, Y.M.; Lee, I.F.; Delwar, Z.; Ding, J.; Liu, G.; Liu, X.; Bu, X.; Sun, Y.; Samudio, I.; et al. Targeting Carcinoembryonic Antigen-Expressing Tumors Using a Novel Transcriptional and Translational Dual-Regulated Oncolytic Herpes Simplex Virus Type 1. Mol. Ther. Oncolytics 2023, 28, 334–348. [Google Scholar] [CrossRef]
  59. Chouljenko, D.V.; Ding, J.; Lee, I.F.; Murad, Y.M.; Bu, X.; Liu, G.; Delwar, Z.; Sun, Y.; Yu, S.; Samudio, I.; et al. Induction of Durable Antitumor Response by a Novel Oncolytic Herpesvirus Expressing Multiple Immunomodulatory Transgenes. Biomedicines 2020, 8, 484. [Google Scholar] [CrossRef] [PubMed]
  60. Liu, S.; Li, F.; Ma, Q.; Du, M.; Wang, H.; Zhu, Y.; Deng, L.; Gao, W.; Wang, C.; Liu, Y.; et al. Ox40l-Armed Oncolytic Virus Boosts T-Cell Response and Remodels Tumor Microenvironment for Pancreatic Cancer Treatment. Theranostics 2023, 13, 4016–4029. [Google Scholar] [CrossRef]
  61. Rosewell Shaw, A.; Suzuki, M. Oncolytic Viruses Partner with T-Cell Therapy for Solid Tumor Treatment. Front. Immunol. 2018, 9, 2103. [Google Scholar] [CrossRef] [PubMed]
  62. Deng, X.; Shen, Y.; Yi, M.; Zhang, C.; Zhao, B.; Zhong, G.; Weiyang, L.; Xue, D.; Leng, Q.; Ding, J.; et al. Combination of Novel Oncolytic Herpesvirus with Paclitaxel as an Efficient Strategy for Breast Cancer Therapy. J. Med. Virol. 2023, 95, e28768. [Google Scholar] [CrossRef] [PubMed]
  63. Wang, L.; Zhou, X.; Chen, X.; Liu, Y.; Huang, Y.; Cheng, Y.; Ren, P.; Zhao, J.; Zhou, G.G. Enhanced Therapeutic Efficacy for Glioblastoma Immunotherapy with an Oncolytic Herpes Simplex Virus Armed with Anti-Pd-1 Antibody and Il-12. Mol. Ther. Oncol. 2024, 32, 200799. [Google Scholar] [CrossRef]
  64. Zhang, N.; Li, J.; Yu, J.; Wan, Y.; Zhang, C.; Zhang, H.; Cao, Y. Construction of an Il12 and Cxcl11 Armed Oncolytic Herpes Simplex Virus Using the Crispr/Cas9 System for Colon Cancer Treatment. Virus Res. 2023, 323, 198979. [Google Scholar] [CrossRef] [PubMed]
  65. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The Next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef]
  66. Yu, X.; Li, T.; Xia, Y.; Lei, J.; Wang, Y.; Zhang, L. Herpes Simplex Virus Type 1 Vp22-Mediated Intercellular Delivery of Pten Increases the Antitumor Activity of Pten in Esophageal Squamous Cell Carcinoma Cells in Vitro and in Vivo. Oncol. Rep. 2016, 35, 3034–3040. [Google Scholar] [CrossRef]
  67. Russell, L.; Swanner, J.; Jaime-Ramirez, A.C.; Wang, Y.; Sprague, A.; Banasavadi-Siddegowda, Y.; Yoo, J.Y.; Sizemore, G.M.; Kladney, R.; Zhang, J.; et al. Pten Expression by an Oncolytic Herpesvirus Directs T-Cell Mediated Tumor Clearance. Nat. Commun. 2018, 9, 5006. [Google Scholar] [CrossRef]
  68. Sahu, U.; Mullarkey, M.P.; Pei, G.; Zhao, Z.; Hong, B.; Kaur, B. Ohsv-P10 Reduces Glioma Stem Cell Enrichment after Oncolytic Hsv Therapy. Mol. Ther. Oncolytics 2023, 29, 30–41. [Google Scholar] [CrossRef]
  69. Wang, X.; Zhu, H.; Wang, X.; Liu, X.; Ma, Z. Oncolytic Property of Hsv-1 Recombinant Viruses Carrying the P53 Gene. Zhonghua Yi Xue Za Zhi 2016, 96, 370–374. [Google Scholar]
  70. Nyberg, P.; Xie, L.; Kalluri, R. Endogenous Inhibitors of Angiogenesis. Cancer Res. 2005, 65, 3967–3979. [Google Scholar] [CrossRef]
  71. Nimmerjahn, F.; Gordan, S.; Lux, A. Fcγr Dependent Mechanisms of Cytotoxic, Agonistic, and Neutralizing Antibody Activities. Trends Immunol. 2015, 36, 325–336. [Google Scholar] [CrossRef]
  72. Waldman, A.D.; Fritz, J.M.; Lenardo, M.J. A Guide to Cancer Immunotherapy: From T Cell Basic Science to Clinical Practice. Nat. Rev. Immunol. 2020, 20, 651–668. [Google Scholar] [CrossRef]
  73. Passaro, C.; Alayo, Q.; De Laura, I.; McNulty, J.; Grauwet, K.; Ito, H.; Bhaskaran, V.; Mineo, M.; Lawler, S.E.; Shah, K.; et al. Arming an Oncolytic Herpes Simplex Virus Type 1 with a Single-Chain Fragment Variable Antibody against Pd-1 for Experimental Glioblastoma Therapy. Clin. Cancer Res. 2019, 25, 290–299. [Google Scholar] [CrossRef]
  74. Huang, S.; Hu, H.; Tang, G.; Liu, K.; Luo, Z.; Zeng, W. An Oncolytic Herpes Simplex Virus Type 1 Strain Expressing a Single-Chain Variable Region Antibody Fragment against Pd-1 and a Pi3k Inhibitor Synergize to Elicit Antitumor Immunity in Ovarian Cancer. Arch. Virol. 2023, 168, 128. [Google Scholar] [CrossRef]
  75. Ju, F.; Luo, Y.; Lin, C.; Jia, X.; Xu, Z.; Tian, R.; Lin, Y.; Zhao, M.; Chang, Y.; Huang, X.; et al. Oncolytic Virus Expressing Pd-1 Inhibitors Activates a Collaborative Intratumoral Immune Response to Control Tumor and Synergizes with Ctla-4 or Tim-3 Blockade. J. Immunother Cancer 2022, 10, e004762. [Google Scholar] [CrossRef] [PubMed]
  76. Xie, X.; Lv, J.; Zhu, W.; Tian, C.; Li, J.; Liu, J.; Zhou, H.; Sun, C.; Hu, Z.; Li, X. The Combination Therapy of Oncolytic Hsv-1 Armed with Anti-Pd-1 Antibody and Il-12 Enhances Anti-Tumor Efficacy. Transl. Oncol. 2022, 15, 101287. [Google Scholar] [CrossRef] [PubMed]
  77. Tian, C.; Liu, J.; Zhou, H.; Li, J.; Sun, C.; Zhu, W.; Yin, Y.; Li, X. Enhanced Anti-Tumor Response Elicited by a Novel Oncolytic Hsv-1 Engineered with an Anti-Pd-1 Antibody. Cancer Lett. 2021, 518, 49–58. [Google Scholar] [CrossRef]
  78. Zhu, Y.; Hu, X.; Feng, L.; Yang, Z.; Zhou, L.; Duan, X.; Cheng, S.; Zhang, W.; Liu, B.; Zhang, K. Enhanced Therapeutic Efficacy of a Novel Oncolytic Herpes Simplex Virus Type 2 Encoding an Antibody against Programmed Cell Death 1. Mol. Ther. Oncolytics 2019, 15, 201–213. [Google Scholar] [CrossRef]
  79. Delwar, Z.; Tatsiy, O.; Chouljenko, D.V.; Lee, I.F.; Liu, G.; Liu, X.; Bu, L.; Ding, J.; Singh, M.; Murad, Y.M.; et al. Prophylactic Vaccination and Intratumoral Boost with Her2-Expressing Oncolytic Herpes Simplex Virus Induces Robust and Persistent Immune Response against Her2-Positive Tumor Cells. Vaccines 2023, 11, 1805. [Google Scholar] [CrossRef]
  80. Gianni, T.; Leoni, V.; Sanapo, M.; Parenti, F.; Bressanin, D.; Barboni, C.; Zaghini, A.; Campadelli-Fiume, G.; Vannini, A. Genotype of Immunologically Hot or Cold Tumors Determines the Antitumor Immune Response and Efficacy by Fully Virulent Retargeted Ohsv. Viruses 2021, 13, 1747. [Google Scholar] [CrossRef] [PubMed]
  81. Vannini, A.; Leoni, V.; Sanapo, M.; Gianni, T.; Giordani, G.; Gatta, V.; Barboni, C.; Zaghini, A.; Campadelli-Fiume, G. Immunotherapeutic Efficacy of Retargeted Ohsvs Designed for Propagation in an Ad Hoc Cell Line. Cancers 2021, 13, 266. [Google Scholar] [CrossRef]
  82. Froechlich, G.; Caiazza, C.; Gentile, C.; D’Alise, A.M.; De Lucia, M.; Langone, F.; Leoni, G.; Cotugno, G.; Scisciola, V.; Nicosia, A.; et al. Integrity of the Antiviral Sting-Mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus. Cancers 2020, 12, 3407. [Google Scholar] [CrossRef]
  83. Leoni, V.; Petrovic, B.; Gianni, T.; Gatta, V.; Campadelli-Fiume, G. Simultaneous Insertion of Two Ligands in Gd for Cultivation of Oncolytic Herpes Simplex Viruses in Noncancer Cells and Retargeting to Cancer Receptors. J. Virol. 2018, 92, e02132-17. [Google Scholar] [CrossRef]
  84. Yarden, Y.; Sliwkowski, M.X. Untangling the Erbb Signalling Network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127–137. [Google Scholar] [CrossRef]
  85. Mascia, F.; Cataisson, C.; Lee, T.C.; Threadgill, D.; Mariani, V.; Amerio, P.; Chandrasekhara, C.; Souto Adeva, G.; Girolomoni, G.; Yuspa, S.H.; et al. Egfr Regulates the Expression of Keratinocyte-Derived Granulocyte/Macrophage Colony-Stimulating Factor in Vitro and in Vivo. J. Investig. Dermatol. 2010, 130, 682–693. [Google Scholar] [CrossRef]
  86. Tian, L.; Xu, B.; Chen, Y.; Li, Z.; Wang, J.; Zhang, J.; Ma, R.; Cao, S.; Hu, W.; Chiocca, E.A.; et al. Specific Targeting of Glioblastoma with an Oncolytic Virus Expressing a Cetuximab-Ccl5 Fusion Protein Via Innate and Adaptive Immunity. Nat. Cancer 2022, 3, 1318–1335. [Google Scholar] [CrossRef]
  87. Appolloni, I.; Alessandrini, F.; Menotti, L.; Avitabile, E.; Marubbi, D.; Piga, N.; Ceresa, D.; Piaggio, F.; Campadelli-Fiume, G.; Malatesta, P. Specificity, Safety, Efficacy of Egfrviii-Retargeted Oncolytic Hsv for Xenotransplanted Human Glioblastoma. Viruses 2021, 13, 1677. [Google Scholar] [CrossRef]
  88. He, S.; Han, J. Manipulation of Host Cell Death Pathways by Herpes Simplex Virus. Curr. Top. Microbiol. Immunol. 2023, 442, 85–103. [Google Scholar] [PubMed]
  89. Todo, T.; Ito, H.; Ino, Y.; Ohtsu, H.; Ota, Y.; Shibahara, J.; Tanaka, M. Intratumoral Oncolytic Herpes Virus G47∆ for Residual or Recurrent Glioblastoma: A Phase 2 Trial. Nat. Med. 2022, 28, 1630–1639. [Google Scholar] [CrossRef] [PubMed]
  90. Bommareddy, P.K.; Wakimoto, H.; Martuza, R.L.; Kaufman, H.L.; Rabkin, S.D.; Saha, D. Oncolytic Herpes Simplex Virus Expressing Il-2 Controls Glioblastoma Growth and Improves Survival. J. Immunother Cancer 2024, 12, e008880. [Google Scholar] [CrossRef]
  91. Saha, D.; Rabkin, S.D.; Martuza, R.L. Temozolomide Antagonizes Oncolytic Immunovirotherapy in Glioblastoma. J. Immunother Cancer 2020, 8, e000345. [Google Scholar] [CrossRef]
  92. Ghouse, S.M.; Nguyen, H.M.; Bommareddy, P.K.; Guz-Montgomery, K.; Saha, D. Oncolytic Herpes Simplex Virus Encoding Il12 Controls Triple-Negative Breast Cancer Growth and Metastasis. Front. Oncol. 2020, 10, 384. [Google Scholar] [CrossRef]
  93. Saha, D.; Wakimoto, H.; Peters, C.W.; Antoszczyk, S.J.; Rabkin, S.D.; Martuza, R.L. Combinatorial Effects of Vegfr Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models. Clin. Cancer Res. 2018, 24, 3409–3422. [Google Scholar] [CrossRef]
  94. Saha, D.; Martuza, R.L.; Rabkin, S.D. Oncolytic Herpes Simplex Virus Immunovirotherapy in Combination with Immune Checkpoint Blockade to Treat Glioblastoma. Immunotherapy 2018, 10, 779–786. [Google Scholar] [CrossRef]
  95. Saha, D.; Martuza, R.L.; Rabkin, S.D. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade. Cancer Cell 2017, 32, 253–267.e255. [Google Scholar] [CrossRef]
  96. Antoszczyk, S.; Spyra, M.; Mautner, V.F.; Kurtz, A.; Stemmer-Rachamimov, A.O.; Martuza, R.L.; Rabkin, S.D. Treatment of Orthotopic Malignant Peripheral Nerve Sheath Tumors with Oncolytic Herpes Simplex Virus. Neuro Oncol. 2014, 16, 1057–1066. [Google Scholar] [CrossRef]
  97. Tazzyman, S.; Stewart, G.R.; Yeomans, J.; Linford, A.; Lath, D.; Conner, J.; Muthana, M.; Chantry, A.D.; Lawson, M.A. Hsv1716 Prevents Myeloma Cell Regrowth When Combined with Bortezomib in Vitro and Significantly Reduces Systemic Tumor Growth in Mouse Models. Viruses 2023, 15, 603. [Google Scholar] [CrossRef]
  98. Bozhanova, G.; Hassan, J.; Appleton, L.; Jennings, V.; Foo, S.; McLaughlin, M.; Chan Wah Hak, C.M.; Patin, E.C.; Crespo-Rodriguez, E.; Baker, G.; et al. Cd4 T Cell Dynamics Shape the Immune Response to Combination Oncolytic Herpes Virus and Braf Inhibitor Therapy for Melanoma. J. Immunother Cancer 2022, 10, e004410. [Google Scholar] [CrossRef]
  99. Kwan, A.; Winder, N.; Atkinson, E.; Al-Janabi, H.; Allen, R.J.; Hughes, R.; Moamin, M.; Louie, R.; Evans, D.; Hutchinson, M.; et al. Macrophages Mediate the Antitumor Effects of the Oncolytic Virus Hsv1716 in Mammary Tumors. Mol. Cancer Ther. 2021, 20, 589–601. [Google Scholar] [CrossRef] [PubMed]
  100. Hutzen, B.; Chen, C.Y.; Wang, P.Y.; Sprague, L.; Swain, H.M.; Love, J.; Conner, J.; Boon, L.; Cripe, T.P. Tgf-Β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma. Mol. Ther. Oncolytics 2017, 7, 17–26. [Google Scholar] [CrossRef]
  101. Currier, M.A.; Sprague, L.; Rizvi, T.A.; Nartker, B.; Chen, C.Y.; Wang, P.Y.; Hutzen, B.J.; Franczek, M.R.; Patel, A.V.; Chaney, K.E.; et al. Aurora a Kinase Inhibition Enhances Oncolytic Herpes Virotherapy through Cytotoxic Synergy and Innate Cellular Immune Modulation. Oncotarget 2017, 8, 17412–17427. [Google Scholar] [CrossRef] [PubMed]
  102. Cockle, J.V.; Brüning-Richardson, A.; Scott, K.J.; Thompson, J.; Kottke, T.; Morrison, E.; Ismail, A.; Carcaboso, A.M.; Rose, A.; Selby, P.; et al. Oncolytic Herpes Simplex Virus Inhibits Pediatric Brain Tumor Migration and Invasion. Mol. Ther. Oncolytics 2017, 5, 75–86. [Google Scholar] [CrossRef]
  103. Braidwood, L.; Learmonth, K.; Graham, A.; Conner, J. Potent Efficacy Signals from Systemically Administered Oncolytic Herpes Simplex Virus (Hsv1716) in Hepatocellular Carcinoma Xenograft Models. J. Hepatocell Carcinoma 2014, 1, 149–161. [Google Scholar]
  104. Friedman, G.K.; Moore, B.P.; Nan, L.; Kelly, V.M.; Etminan, T.; Langford, C.P.; Xu, H.; Han, X.; Markert, J.M.; Beierle, E.A.; et al. Pediatric Medulloblastoma Xenografts Including Molecular Subgroup 3 and Cd133+ and Cd15+ Cells Are Sensitive to Killing by Oncolytic Herpes Simplex Viruses. Neuro Oncol. 2016, 18, 227–235. [Google Scholar] [CrossRef]
  105. Song, T.J.; Haddad, D.; Adusumilli, P.; Kim, T.; Stiles, B.; Hezel, M.; Socci, N.D.; Gönen, M.; Fong, Y. Molecular Network Pathways and Functional Analysis of Tumor Signatures Associated with Development of Resistance to Viral Gene Therapy. Cancer Gene Ther. 2012, 19, 38–48. [Google Scholar] [CrossRef]
  106. Thomas, S.; Kuncheria, L.; Roulstone, V.; Kyula, J.N.; Mansfield, D.; Bommareddy, P.K.; Smith, H.; Kaufman, H.L.; Harrington, K.J.; Coffin, R.S. Development of a New Fusion-Enhanced Oncolytic Immunotherapy Platform Based on Herpes Simplex Virus Type 1. J. Immunother Cancer 2019, 7, 214. [Google Scholar] [CrossRef]
  107. Zhang, J.; Wang, J.; Li, M.; Su, X.; Tian, Y.; Wang, P.; Zhou, X.; Jin, G.; Liu, F. Oncolytic Hsv-1 Suppresses Cell Invasion through Downregulating Sp1 in Experimental Glioblastoma. Cell. Signal. 2023, 103, 110581. [Google Scholar] [CrossRef]
  108. Eissa, I.R.; Naoe, Y.; Bustos-Villalobos, I.; Ichinose, T.; Tanaka, M.; Zhiwen, W.; Mukoyama, N.; Morimoto, T.; Miyajima, N.; Hitoki, H.; et al. Genomic Signature of the Natural Oncolytic Herpes Simplex Virus Hf10 and Its Therapeutic Role in Preclinical and Clinical Trials. Front. Oncol. 2017, 7, 149. [Google Scholar] [CrossRef]
  109. Takano, G.; Esaki, S.; Goshima, F.; Enomoto, A.; Hatano, Y.; Ozaki, H.; Watanabe, T.; Sato, Y.; Kawakita, D.; Murakami, S.; et al. Oncolytic Activity of Naturally Attenuated Herpes-Simplex Virus Hf10 against an Immunocompetent Model of Oral Carcinoma. Mol. Ther. Oncolytics 2021, 20, 220–227. [Google Scholar] [CrossRef]
  110. Esaki, S.; Goshima, F.; Ozaki, H.; Takano, G.; Hatano, Y.; Kawakita, D.; Ijichi, K.; Watanabe, T.; Sato, Y.; Murata, T.; et al. Oncolytic Activity of Hf10 in Head and Neck Squamous Cell Carcinomas. Cancer Gene Ther. 2020, 27, 585–598. [Google Scholar] [CrossRef] [PubMed]
  111. Wu, Z.; Ichinose, T.; Naoe, Y.; Matsumura, S.; Villalobos, I.B.; Eissa, I.R.; Yamada, S.; Miyajima, N.; Morimoto, D.; Mukoyama, N.; et al. Combination of Cetuximab and Oncolytic Virus Canerpaturev Synergistically Inhibits Human Colorectal Cancer Growth. Mol. Ther. Oncolytics 2019, 13, 107–115. [Google Scholar] [CrossRef]
  112. Tanaka, R.; Goshima, F.; Esaki, S.; Sato, Y.; Murata, T.; Nishiyama, Y.; Watanabe, D.; Kimura, H. The Efficacy of Combination Therapy with Oncolytic Herpes Simplex Virus Hf10 and Dacarbazine in a Mouse Melanoma Model. Am. J. Cancer Res. 2017, 7, 1693–1703. [Google Scholar] [PubMed]
  113. Hotta, Y.; Kasuya, H.; Bustos, I.; Naoe, Y.; Ichinose, T.; Tanaka, M.; Kodera, Y. Curative Effect of Hf10 on Liver and Peritoneal Metastasis Mediated by Host Antitumor Immunity. Oncolytic Virother. 2017, 6, 31–38. [Google Scholar] [PubMed]
  114. Yamamura, K.; Kasuya, H.; Sahin, T.T.; Tan, G.; Hotta, Y.; Tsurumaru, N.; Fukuda, S.; Kanda, M.; Kobayashi, D.; Tanaka, C.; et al. Combination Treatment of Human Pancreatic Cancer Xenograft Models with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib and Oncolytic Herpes Simplex Virus Hf10. Ann. Surg. Oncol. 2014, 21, 691–698. [Google Scholar] [CrossRef]
  115. Liu, T.C.; Wakimoto, H.; Martuza, R.L.; Rabkin, S.D. Herpes Simplex Virus Us3(-) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt Targeting Molecular Therapeutics. Clin. Cancer Res. 2007, 13, 5897–5902. [Google Scholar] [CrossRef]
  116. Nanni, P.; Gatta, V.; Menotti, L.; De Giovanni, C.; Ianzano, M.; Palladini, A.; Grosso, V.; Dall’ora, M.; Croci, S.; Nicoletti, G.; et al. Preclinical Therapy of Disseminated Her-2+ Ovarian and Breast Carcinomas with a Her-2-Retargeted Oncolytic Herpesvirus. PLoS Pathog. 2013, 9, e1003155. [Google Scholar] [CrossRef]
  117. Zhu, W.; Lv, J.; Xie, X.; Tian, C.; Liu, J.; Zhou, H.; Sun, C.; Li, J.; Hu, Z.; Li, X. The Oncolytic Virus Vt09x Optimizes Immune Checkpoint Therapy in Low Immunogenic Melanoma. Immunol. Lett. 2022, 241, 15–22. [Google Scholar] [CrossRef]
  118. Workenhe, S.T.; Ketela, T.; Moffat, J.; Cuddington, B.P.; Mossman, K.L. Genome-Wide Lentiviral Shrna Screen Identifies Serine/Arginine-Rich Splicing Factor 2 as a Determinant of Oncolytic Virus Activity in Breast Cancer Cells. Oncogene 2016, 35, 2465–2474. [Google Scholar] [CrossRef]
  119. Czarnywojtek, A.; Borowska, M.; Dyrka, K.; Van Gool, S.; Sawicka-Gutaj, N.; Moskal, J.; Kościński, J.; Graczyk, P.; Hałas, T.; Lewandowska, A.M.; et al. Glioblastoma Multiforme: The Latest Diagnostics and Treatment Techniques. Pharmacology 2023, 108, 423–431. [Google Scholar] [CrossRef]
  120. Mineta, T.; Rabkin, S.D.; Yazaki, T.; Hunter, W.D.; Martuza, R.L. Attenuated Multi-Mutated Herpes Simplex Virus-1 for the Treatment of Malignant Gliomas. Nat. Med. 1995, 1, 938–943. [Google Scholar] [CrossRef] [PubMed]
  121. Taguchi, S.; Fukuhara, H.; Todo, T. Oncolytic Virus Therapy in Japan: Progress in Clinical Trials and Future Perspectives. Jpn J. Clin. Oncol. 2019, 49, 201–209. [Google Scholar] [CrossRef] [PubMed]
  122. Todo, T.; Ino, Y.; Ohtsu, H.; Shibahara, J.; Tanaka, M. A Phase I/Ii Study of Triple-Mutated Oncolytic Herpes Virus G47∆ in Patients with Progressive Glioblastoma. Nat. Commun. 2022, 13, 4119. [Google Scholar] [CrossRef]
  123. Kazemi Shariat Panahi, H.; Dehhaghi, M.; Lam, S.S.; Peng, W.; Aghbashlo, M.; Tabatabaei, M.; Guillemin, G.J. Oncolytic Viruses as a Promising Therapeutic Strategy against the Detrimental Health Impacts of Air Pollution: The Case of Glioblastoma Multiforme. Semin. Cancer Biol. 2022, 86, 1122–1142. [Google Scholar] [CrossRef]
  124. Kambara, H.; Okano, H.; Chiocca, E.A.; Saeki, Y. An Oncolytic Hsv-1 Mutant Expressing Icp34.5 under Control of a Nestin Promoter Increases Survival of Animals Even When Symptomatic from a Brain Tumor. Cancer Res. 2005, 65, 2832–2839. [Google Scholar] [CrossRef]
  125. Streby, K.A.; Geller, J.I.; Currier, M.A.; Warren, P.S.; Racadio, J.M.; Towbin, A.J.; Vaughan, M.R.; Triplet, M.; Ott-Napier, K.; Dishman, D.J.; et al. Intratumoral Injection of Hsv1716, an Oncolytic Herpes Virus, Is Safe and Shows Evidence of Immune Response and Viral Replication in Young Cancer Patients. Clin. Cancer Res. 2017, 23, 3566–3574. [Google Scholar] [CrossRef]
  126. Estevez-Ordonez, D.; Chagoya, G.; Salehani, A.; Atchley, T.J.; Laskay, N.M.B.; Parr, M.S.; Elsayed, G.A.; Mahavadi, A.K.; Rahm, S.P.; Friedman, G.K.; et al. Immunovirotherapy for the Treatment of Glioblastoma and Other Malignant Gliomas. Neurosurg. Clin. N. Am. 2021, 32, 265–281. [Google Scholar] [CrossRef]
  127. Friedman, G.K.; Nan, L.; Haas, M.C.; Kelly, V.M.; Moore, B.P.; Langford, C.P.; Xu, H.; Han, X.; Beierle, E.A.; Markert, J.M.; et al. Γ134.5-Deleted Hsv-1-Expressing Human Cytomegalovirus Irs1 Gene Kills Human Glioblastoma Cells as Efficiently as Wild-Type Hsv-1 in Normoxia or Hypoxia. Gene Ther. 2015, 22, 348–355. [Google Scholar] [CrossRef] [PubMed]
  128. Bernstock, J.D.; Bag, A.K.; Fiveash, J.; Kachurak, K.; Elsayed, G.; Chagoya, G.; Gessler, F.; Valdes, P.A.; Madan-Swain, A.; Whitley, R.; et al. Design and Rationale for First-in-Human Phase 1 Immunovirotherapy Clinical Trial of Oncolytic Hsv G207 to Treat Malignant Pediatric Cerebellar Brain Tumors. Hum. Gene Ther. 2020, 31, 1132–1139. [Google Scholar] [CrossRef] [PubMed]
  129. Roth, J.C.; Cassady, K.A.; Cody, J.J.; Parker, J.N.; Price, K.H.; Coleman, J.M.; Peggins, J.O.; Noker, P.E.; Powers, N.W.; Grimes, S.D.; et al. Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing Hil-12, after Intracerebral Administration to Aotus Nonhuman Primates. Hum. Gene Ther. Clin. Dev. 2014, 25, 16–27. [Google Scholar] [CrossRef]
  130. Patel, D.M.; Foreman, P.M.; Nabors, L.B.; Riley, K.O.; Gillespie, G.Y.; Markert, J.M. Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered Hsv-1 Expressing Il-12, in Patients with Recurrent/Progressive Glioblastoma Multiforme, Anaplastic Astrocytoma, or Gliosarcoma. Hum. Gene Ther. Clin. Dev. 2016, 27, 69–78. [Google Scholar] [CrossRef]
  131. Killock, D. Skin Cancer: T-Vec Oncolytic Viral Therapy Shows Promise in Melanoma. Nat. Rev. Clin. Oncol. 2015, 12, 438. [Google Scholar] [CrossRef]
  132. Poh, A. First Oncolytic Viral Therapy for Melanoma. Cancer Discov. 2016, 6, 6. [Google Scholar] [CrossRef]
  133. Cavalcante, L.; Chowdhary, A.; Sosman, J.A.; Chandra, S. Combining Tumor Vaccination and Oncolytic Viral Approaches with Checkpoint Inhibitors: Rationale, Pre-Clinical Experience, and Current Clinical Trials in Malignant Melanoma. Am. J. Clin. Dermatol. 2018, 19, 657–670. [Google Scholar] [CrossRef]
  134. Kaufman, H.L.; Kim, D.W.; DeRaffele, G.; Mitcham, J.; Coffin, R.S.; Kim-Schulze, S. Local and Distant Immunity Induced by Intralesional Vaccination with an Oncolytic Herpes Virus Encoding Gm-Csf in Patients with Stage Iiic and Iv Melanoma. Ann. Surg. Oncol. 2010, 17, 718–730. [Google Scholar] [CrossRef]
  135. Spitler, L.E.; Weber, R.W.; Allen, R.E.; Meyer, J.; Cruickshank, S.; Garbe, E.; Lin, H.Y.; Soong, S.J. Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (Gm-Csf, Sargramostim) Administered for 3 Years as Adjuvant Therapy of Stages Ii(T4), Iii, and Iv Melanoma. J. Immunother. 2009, 32, 632–637. [Google Scholar] [CrossRef]
  136. Andtbacka, R.H.; Kaufman, H.L.; Collichio, F.; Amatruda, T.; Senzer, N.; Chesney, J.; Delman, K.A.; Spitler, L.E.; Puzanov, I.; Agarwala, S.S.; et al. Talimogene Laherparepvec Improves Durable Response Rate in Patients with Advanced Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2015, 33, 2780–2788. [Google Scholar] [CrossRef] [PubMed]
  137. Andtbacka, R.H.; Ross, M.; Puzanov, I.; Milhem, M.; Collichio, F.; Delman, K.A.; Amatruda, T.; Zager, J.S.; Cranmer, L.; Hsueh, E.; et al. Patterns of Clinical Response with Talimogene Laherparepvec (T-Vec) in Patients with Melanoma Treated in the Optim Phase Iii Clinical Trial. Ann. Surg. Oncol. 2016, 23, 4169–4177. [Google Scholar] [CrossRef]
  138. Chesney, J.; Puzanov, I.; Collichio, F.; Singh, P.; Milhem, M.M.; Glaspy, J.; Hamid, O.; Ross, M.; Friedlander, P.; Garbe, C.; et al. Randomized, Open-Label Phase Ii Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination with Ipilimumab Versus Ipilimumab Alone in Patients with Advanced, Unresectable Melanoma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 1658–1667. [Google Scholar] [CrossRef]
  139. Everett, A.S.; Pavlidakey, P.G.; Contreras, C.M.; De Los Santos, J.F.; Kim, J.Y.; McKee, S.B.; Kaufman, H.L.; Conry, R.M. Chronic Granulomatous Dermatitis Induced by Talimogene Laherparepvec Therapy of Melanoma Metastases. J. Cutan Pathol. 2018, 45, 48–53. [Google Scholar] [CrossRef]
  140. Wang, Y.; Jin, J.; Li, Y.; Zhou, Q.; Yao, R.; Wu, Z.; Hu, H.; Fang, Z.; Dong, S.; Cai, Q.; et al. Nk Cell Tumor Therapy Modulated by Uv-Inactivated Oncolytic Herpes Simplex Virus Type 2 and Checkpoint Inhibitors. Transl. Res. 2022, 240, 64–86. [Google Scholar] [CrossRef]
  141. Wang, X.; Tian, H.; Chi, Z.; Si, L.; Sheng, X.; Hu, H.; Gu, X.; Li, S.; Li, C.; Lian, B.; et al. Oncolytic Virus Oh2 Extends Survival in Patients with Pd-1 Pretreated Melanoma: Phase Ia/Ib Trial Results and Biomarker Insights. J. Immunother Cancer 2025, 13, e010662. [Google Scholar] [CrossRef]
  142. Hecht, J.R.; Raman, S.S.; Chan, A.; Kalinsky, K.; Baurain, J.F.; Jimenez, M.M.; Garcia, M.M.; Berger, M.D.; Lauer, U.M.; Khattak, A.; et al. Phase Ib Study of Talimogene Laherparepvec in Combination with Atezolizumab in Patients with Triple Negative Breast Cancer and Colorectal Cancer with Liver Metastases. ESMO Open 2023, 8, 100884. [Google Scholar] [CrossRef]
  143. Runcie, K.; Bracero, Y.; Samouha, A.; Manji, G.; Remotti, H.E.; Gonda, T.A.; Saenger, Y. Phase I Study of Intratumoral Injection of Talimogene Laherparepvec for the Treatment of Advanced Pancreatic Cancer. Oncologist 2025, 30, oyae200. [Google Scholar] [CrossRef]
  144. Harrington, K.J.; Kong, A.; Mach, N.; Chesney, J.A.; Fernandez, B.C.; Rischin, D.; Cohen, E.E.W.; Radcliffe, H.S.; Gumuscu, B.; Cheng, J.; et al. Talimogene Laherparepvec and Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (Masterkey-232): A Multicenter, Phase 1b Study. Clin. Cancer Res. 2020, 26, 5153–5161. [Google Scholar] [CrossRef] [PubMed]
  145. Zhang, B.; Huang, J.; Tang, J.; Hu, S.; Luo, S.; Luo, Z.; Zhou, F.; Tan, S.; Ying, J.; Chang, Q.; et al. Intratumoral Oh2, an Oncolytic Herpes Simplex Virus 2, in Patients with Advanced Solid Tumors: A Multicenter, Phase I/Ii Clinical Trial. J. Immunother Cancer 2021, 9, e002224. [Google Scholar] [CrossRef] [PubMed]
  146. Farassati, F.; Yang, A.D.; Lee, P.W. Oncogenes in Ras Signalling Pathway Dictate Host-Cell Permissiveness to Herpes Simplex Virus 1. Nat. Cell Biol. 2001, 3, 745–750. [Google Scholar] [CrossRef]
  147. Smith, K.D.; Mezhir, J.J.; Bickenbach, K.; Veerapong, J.; Charron, J.; Posner, M.C.; Roizman, B.; Weichselbaum, R.R. Activated Mek Suppresses Activation of Pkr and Enables Efficient Replication and in Vivo Oncolysis by Deltagamma(1)34.5 Mutants of Herpes Simplex Virus 1. J. Virol. 2006, 80, 1110–1120. [Google Scholar] [CrossRef]
  148. Ye, Z.Q.; Zou, C.L.; Chen, H.B.; Lv, Q.Y.; Wu, R.Q.; Gu, D.N. Folate-Conjugated Herpes Simplex Virus for Retargeting to Tumor Cells. J. Gene Med. 2020, 22, e3177. [Google Scholar] [CrossRef] [PubMed]
  149. Zottel, A.; Videtič Paska, A.; Jovčevska, I. Nanotechnology Meets Oncology: Nanomaterials in Brain Cancer Research, Diagnosis and Therapy. Materials 2019, 12, 1588. [Google Scholar] [CrossRef]
  150. Farhat, W.; Yeung, V.; Kahale, F.; Parekh, M.; Cortinas, J.; Chen, L.; Ross, A.E.; Ciolino, J.B. Doxorubicin-Loaded Extracellular Vesicles Enhance Tumor Cell Death in Retinoblastoma. Bioengineering 2022, 9, 671. [Google Scholar] [CrossRef]
  151. Liau, L.M.; Ashkan, K.; Tran, D.D.; Campian, J.L.; Trusheim, J.E.; Cobbs, C.S.; Heth, J.A.; Salacz, M.; Taylor, S.; D’Andre, S.D.; et al. First Results on Survival from a Large Phase 3 Clinical Trial of an Autologous Dendritic Cell Vaccine in Newly Diagnosed Glioblastoma. J. Transl. Med. 2018, 16, 142. [Google Scholar] [CrossRef]
  152. Blass, E.; Ott, P.A. Advances in the Development of Personalized Neoantigen-Based Therapeutic Cancer Vaccines. Nat. Rev. Clin. Oncol. 2021, 18, 215–229. [Google Scholar] [CrossRef]
  153. Howard, F.H.N.; Al-Janabi, H.; Patel, P.; Cox, K.; Smith, E.; Vadakekolathu, J.; Pockley, A.G.; Conner, J.; Nohl, J.F.; Allwood, D.A.; et al. Nanobugs as Drugs: Bacterial Derived Nanomagnets Enhance Tumor Targeting and Oncolytic Activity of Hsv-1 Virus. Small 2022, 18, e2104763. [Google Scholar] [CrossRef]
  154. Lewinski, N.; Colvin, V.; Drezek, R. Cytotoxicity of Nanoparticles. Small 2008, 4, 26–49. [Google Scholar] [CrossRef]
  155. Ferraris, C.; Cavalli, R.; Panciani, P.P.; Battaglia, L. Overcoming the Blood-Brain Barrier: Successes and Challenges In developing Nanoparticle-Mediated Drug Delivery Systems for the Treatment of Brain Tumours. Int. J. Nanomed. 2020, 15, 2999–3022. [Google Scholar] [CrossRef]
  156. Ghasemi Darestani, N.; Gilmanova, A.I.; Al-Gazally, M.E.; Zekiy, A.O.; Ansari, M.J.; Zabibah, R.S.; Jawad, M.A.; Al-Shalah, S.A.J.; Rizaev, J.A.; Alnassar, Y.S.; et al. Mesenchymal Stem Cell-Released Oncolytic Virus: An Innovative Strategy for Cancer Treatment. Cell Commun. Signal 2023, 21, 43. [Google Scholar] [CrossRef]
  157. Ghaleh, H.E.G.; Vakilzadeh, G.; Zahiri, A.; Farzanehpour, M. Investigating the Potential of Oncolytic Viruses for Cancer Treatment Via Msc Delivery. Cell Commun. Signal 2023, 21, 228. [Google Scholar] [CrossRef] [PubMed]
  158. Shi, Y.; Zhang, J.; Li, Y.; Feng, C.; Shao, C.; Shi, Y.; Fang, J. Engineered Mesenchymal Stem/Stromal Cells against Cancer. Cell Death Dis. 2025, 16, 113. [Google Scholar] [CrossRef] [PubMed]
  159. Salmasi, Z.; Hashemi, M.; Mahdipour, E.; Nourani, H.; Abnous, K.; Ramezani, M. Mesenchymal Stem Cells Engineered by Modified Polyethylenimine Polymer for Targeted Cancer Gene Therapy, in Vitro and in Vivo. Biotechnol. Prog. 2020, 36, e3025. [Google Scholar] [CrossRef]
  160. Jacobs, S.A.; Roobrouck, V.D.; Verfaillie, C.M.; Van Gool, S.W. Immunological Characteristics of Human Mesenchymal Stem Cells and Multipotent Adult Progenitor Cells. Immunol. Cell Biol. 2013, 91, 32–39. [Google Scholar] [CrossRef]
  161. Corcione, A.; Benvenuto, F.; Ferretti, E.; Giunti, D.; Cappiello, V.; Cazzanti, F.; Risso, M.; Gualandi, F.; Mancardi, G.L.; Pistoia, V.; et al. Human Mesenchymal Stem Cells Modulate B-Cell Functions. Blood 2006, 107, 367–372. [Google Scholar] [CrossRef]
  162. Franquesa, M.; Hoogduijn, M.J.; Bestard, O.; Grinyó, J.M. Immunomodulatory Effect of Mesenchymal Stem Cells on B Cells. Front. Immunol. 2012, 3, 212. [Google Scholar] [CrossRef]
  163. Najar, M.; Raicevic, G.; Fayyad-Kazan, H.; Bron, D.; Toungouz, M.; Lagneaux, L. Mesenchymal Stromal Cells and Immunomodulation: A Gathering of Regulatory Immune Cells. Cytotherapy 2016, 18, 160–171. [Google Scholar] [CrossRef]
  164. Ali, S.; Xia, Q.; Muhammad, T.; Liu, L.; Meng, X.; Bars-Cortina, D.; Khan, A.A.; Huang, Y.; Dong, L. Glioblastoma Therapy: Rationale for a Mesenchymal Stem Cell-Based Vehicle to Carry Recombinant Viruses. Stem Cell Rev. Rep. 2022, 18, 523–543. [Google Scholar] [CrossRef]
  165. Leoni, V.; Gatta, V.; Palladini, A.; Nicoletti, G.; Ranieri, D.; Dall’Ora, M.; Grosso, V.; Rossi, M.; Alviano, F.; Bonsi, L.; et al. Systemic Delivery of Her2-Retargeted Oncolytic-Hsv by Mesenchymal Stromal Cells Protects from Lung and Brain Metastases. Oncotarget 2015, 6, 34774–34787. [Google Scholar] [CrossRef]
  166. Mosallaei, M.; Simonian, M.; Ehtesham, N.; Karimzadeh, M.R.; Vatandoost, N.; Negahdari, B.; Salehi, R. Genetically Engineered Mesenchymal Stem Cells: Targeted Delivery of Immunomodulatory Agents for Tumor Eradication. Cancer Gene Ther. 2020, 27, 854–868. [Google Scholar] [CrossRef]
  167. Duebgen, M.; Martinez-Quintanilla, J.; Tamura, K.; Hingtgen, S.; Redjal, N.; Wakimoto, H.; Shah, K. Stem Cells Loaded with Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy. J. Natl. Cancer Inst. 2014, 106, dju090. [Google Scholar] [CrossRef]
  168. Du, W.; Seah, I.; Bougazzoul, O.; Choi, G.; Meeth, K.; Bosenberg, M.W.; Wakimoto, H.; Fisher, D.; Shah, K. Stem Cell-Released Oncolytic Herpes Simplex Virus Has Therapeutic Efficacy in Brain Metastatic Melanomas. Proc. Natl. Acad. Sci. USA 2017, 114, E6157–E6165. [Google Scholar] [CrossRef]
  169. Mahasa, K.J.; de Pillis, L.; Ouifki, R.; Eladdadi, A.; Maini, P.; Yoon, A.R.; Yun, C.O. Mesenchymal Stem Cells Used as Carrier Cells of Oncolytic Adenovirus Results in Enhanced Oncolytic Virotherapy. Sci. Rep. 2020, 10, 425. [Google Scholar] [CrossRef]
  170. Montoto-Meijide, R.; Meijide-Faílde, R.; Díaz-Prado, S.M.; Montoto-Marqués, A. Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review. Int. J. Mol. Sci. 2023, 24, 11719. [Google Scholar] [CrossRef]
  171. Piekarska, K.; Urban-Wójciuk, Z.; Kurkowiak, M.; Pelikant-Małecka, I.; Schumacher, A.; Sakowska, J.; Spodnik, J.H.; Arcimowicz, Ł.; Zielińska, H.; Tymoniuk, B.; et al. Mesenchymal Stem Cells Transfer Mitochondria to Allogeneic Tregs in an Hla-Dependent Manner Improving Their Immunosuppressive Activity. Nat. Commun. 2022, 13, 856. [Google Scholar] [CrossRef]
  172. Qi, Z.; Long, X.; Liu, J.; Cheng, P. Glioblastoma Microenvironment and Its Reprogramming by Oncolytic Virotherapy. Front. Cell Neurosci. 2022, 16, 819363. [Google Scholar] [CrossRef]
  173. Bommareddy, P.K.; Shettigar, M.; Kaufman, H.L. Integrating Oncolytic Viruses in Combination Cancer Immunotherapy. Nat. Rev. Immunol. 2018, 18, 498–513. [Google Scholar] [CrossRef]
  174. Roy, D.G.; Bell, J.C. Cell Carriers for Oncolytic Viruses: Current Challenges and Future Directions. Oncolytic Virother. 2013, 2, 47–56. [Google Scholar]
  175. Zheng, M.; Huang, J.; Tong, A.; Yang, H. Oncolytic Viruses for Cancer Therapy: Barriers and Recent Advances. Mol. Ther. Oncolytics 2019, 15, 234–247. [Google Scholar] [CrossRef]
  176. Kuczynski, E.A.; Vermeulen, P.B.; Pezzella, F.; Kerbel, R.S.; Reynolds, A.R. Vessel Co-Option in Cancer. Nat. Rev. Clin. Oncol. 2019, 16, 469–493. [Google Scholar] [CrossRef]
  177. Huang, D.; Jin, Y.H.; Weng, H.; Huang, Q.; Zeng, X.T.; Wang, X.H. Combination of Intravesical Bacille Calmette-Guérin and Chemotherapy Vs. Bacille Calmette-Guérin Alone in Non-Muscle Invasive Bladder Cancer: A Meta-Analysis. Front. Oncol. 2019, 9, 121. [Google Scholar] [CrossRef]
  178. Goradel, N.H.; Baker, A.T.; Arashkia, A.; Ebrahimi, N.; Ghorghanlu, S.; Negahdari, B. Oncolytic Virotherapy: Challenges and Solutions. Curr. Probl. Cancer 2021, 45, 100639. [Google Scholar] [CrossRef]
  179. Li, L.; Liu, S.; Han, D.; Tang, B.; Ma, J. Delivery and Biosafety of Oncolytic Virotherapy. Front. Oncol. 2020, 10, 475. [Google Scholar] [CrossRef]
  180. Howard, F.; Muthana, M. Designer Nanocarriers for Navigating the Systemic Delivery of Oncolytic Viruses. Nanomedicine 2020, 15, 93–110. [Google Scholar] [CrossRef]
  181. Rossmeisl, J.H. Novel Treatments for Brain Tumors. Vet. Clin. N. Am. Small Anim. Pract. 2025, 55, 81–94. [Google Scholar] [CrossRef]
  182. Italiya, K.S.; Mullins-Dansereau, V.; Geoffroy, K.; Gilchrist, V.H.; Alain, T.; Bourgeois-Daigneault, M.C.; Yu, F. Ultrasound and Microbubble Mediated Delivery of Virus-Sensitizing Drugs Improves in Vitro Oncolytic Virotherapy against Breast Cancer Cells. Ultrasound Med. Biol. 2025, 51, 1124–1133. [Google Scholar] [CrossRef]
  183. Shmulevitz, M.; Gujar, S.A.; Ahn, D.G.; Mohamed, A.; Lee, P.W. Reovirus Variants with Mutations in Genome Segments S1 and L2 Exhibit Enhanced Virion Infectivity and Superior Oncolysis. J. Virol. 2012, 86, 7403–7413. [Google Scholar] [CrossRef]
  184. Ungerechts, G.; Bossow, S.; Leuchs, B.; Holm, P.S.; Rommelaere, J.; Coffey, M.; Coffin, R.; Bell, J.; Nettelbeck, D.M. Moving Oncolytic Viruses into the Clinic: Clinical-Grade Production, Purification, and Characterization of Diverse Oncolytic Viruses. Mol. Ther. Methods Clin. Dev. 2016, 3, 16018. [Google Scholar] [CrossRef]
  185. Mendoza, E.J.; Manguiat, K.; Wood, H.; Drebot, M. Two Detailed Plaque Assay Protocols for the Quantification of Infectious Sars-Cov-2. Curr. Protoc. Microbiol. 2020, 57, ecpmc105. [Google Scholar] [CrossRef] [PubMed]
  186. Gujar, S.; Pol, J.G.; Kumar, V.; Lizarralde-Guerrero, M.; Konda, P.; Kroemer, G.; Bell, J.C. Tutorial: Design, Production and Testing of Oncolytic Viruses for Cancer Immunotherapy. Nat. Protoc. 2024, 19, 2540–2570. [Google Scholar] [CrossRef]
  187. Onnockx, S.; Baldo, A.; Pauwels, K. Oncolytic Viruses: An Inventory of Shedding Data from Clinical Trials and Elements for the Environmental Risk Assessment. Vaccines 2023, 11, 1448. [Google Scholar] [CrossRef]
  188. Eisenman, D.; Swindle, S. Fda Guidance on Shedding and Environmental Impact in Clinical Trials Involving Gene Therapy Products. Appl. Biosaf. 2022, 27, 191–197. [Google Scholar] [CrossRef] [PubMed]
  189. Damerval, M.; Fagnoni-Legat, C.; Louvrier, A.; Fischer, S.; Limat, S.; Clairet, A.L.; Nerich, V.; Madelaine, I.; Kroemer, M. Atmp Environmental Exposure Assessment in European Healthcare Settings: A Systematic Review of the Literature. Front. Med. 2021, 8, 713047. [Google Scholar] [CrossRef]
  190. Salazar-Fontana, L.I. A Regulatory Risk-Based Approach to Atmp/Cgt Development: Integrating Scientific Challenges with Current Regulatory Expectations. Front. Med. 2022, 9, 855100. [Google Scholar] [CrossRef]
  191. Chowaniec, H.; Ślubowska, A.; Mroczek, M.; Borowczyk, M.; Braszka, M.; Dworacki, G.; Dobosz, P.; Wichtowski, M. New Hopes for the Breast Cancer Treatment: Perspectives on the Oncolytic Virus Therapy. Front. Immunol. 2024, 15, 1375433. [Google Scholar] [CrossRef]
  192. Ferguson, M.S.; Lemoine, N.R.; Wang, Y. Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles. Adv. Virol. 2012, 2012, 805629. [Google Scholar] [CrossRef]
  193. Stoermer, K.A.; Morrison, T.E. Complement and Viral Pathogenesis. Virology 2011, 411, 362–373. [Google Scholar] [CrossRef] [PubMed]
  194. He, B.; Gao, R.; Lv, S.; Chen, A.; Huang, J.; Wang, L.; Feng, Y.; Feng, J.; Liu, B.; Lei, J.; et al. Cancer Cell Employs a Microenvironmental Neural Signal Trans-Activating Nucleus-Mitochondria Coordination to Acquire Stemness. Signal Transduct. Target Ther. 2023, 8, 275. [Google Scholar] [CrossRef]
  195. Yun, C.O. Overcoming the Extracellular Matrix Barrier to Improve Intratumoral Spread and Therapeutic Potential of Oncolytic Virotherapy. Curr. Opin. Mol. Ther. 2008, 10, 356–361. [Google Scholar] [PubMed]
  196. Ebrahimi, S.; Makvandi, M.; Abbasi, S.; Azadmanesh, K.; Teimoori, A. Developing Oncolytic Herpes Simplex Virus Type 1 through Ul39 Knockout by Crispr-Cas9. Iran J. Basic Med. Sci. 2020, 23, 937–944. [Google Scholar]
  197. Hu, Z.; Liu, W.; Liu, J.; Zhou, H.; Sun, C.; Guo, X.; Zhu, C.; Shao, M.; Wang, S.; Wei, L.; et al. The Anti-Tumor Efficacy of a Recombinant Oncolytic Herpes Simplex Virus Mediated Crispr/Cas9 Delivery Targeting in Hpv16-Positive Cervical Cancer. Antivir. Res. 2024, 232, 106035. [Google Scholar] [CrossRef]
Figure 1. Key milestones in oncolytic herpes simplex virus (oHSV) therapy.
Figure 1. Key milestones in oncolytic herpes simplex virus (oHSV) therapy.
Vaccines 13 00880 g001
Figure 2. Main mechanisms of tumor cell killing by oncolytic viruses. Oncolysis: Oncolytic viruses replicate and proliferate within tumor cells, leading to cellular lysis. Anti-tumor response: Oncolytic viruses can deliver and release exogenous molecules, activating the host to generate an anti-tumor immune response. Inhibit angiogenesis: Oncolytic viruses can infect tumor-associated vascular endothelial cells, thereby inhibiting tumor angiogenesis. TAA: tumor-associated antigens; PAMPs: Pathogen-Associated Molecular Patterns; DAMPs: Damage-Associated Molecular Patterns.
Figure 2. Main mechanisms of tumor cell killing by oncolytic viruses. Oncolysis: Oncolytic viruses replicate and proliferate within tumor cells, leading to cellular lysis. Anti-tumor response: Oncolytic viruses can deliver and release exogenous molecules, activating the host to generate an anti-tumor immune response. Inhibit angiogenesis: Oncolytic viruses can infect tumor-associated vascular endothelial cells, thereby inhibiting tumor angiogenesis. TAA: tumor-associated antigens; PAMPs: Pathogen-Associated Molecular Patterns; DAMPs: Damage-Associated Molecular Patterns.
Vaccines 13 00880 g002
Table 1. Overview of globally marketed oncolytic virus drugs.
Table 1. Overview of globally marketed oncolytic virus drugs.
Drug NameYear of ApprovalViral VectorTherapeutic TargetIndicationsCompany
Rigvir [8]2004ECHO virus/Melanoma, colorectal cancerLatima, Riga, Latvia
H101 (Oncorine) [9]2005Human adenovirus-5E1B-55kDa, E3-19kDaHead and neck cancerSunway Biotech, Shanghai, China
T-VEC (Lmlygic) [4]2015Herpes simplex virus-1Deletion of ICP34.5, ICP47; insertion of hGM-CSFAdvanced melanomaAmgen, Thousand Oaks, CA, USA
G47Δ (Delytact) [5]2021Herpes simplex virus-1Deletion of ICP34.5, ICP47; insertion of LacZMalignant glioma, primary brain tumorDaiichi Sankyo, Tokyo, Japan
Adstiladrin [10]2022Non-replicating
adenovirus
Insertion of IFN-α2bNon-muscle invasive bladder cancerFerring, Parsippany, NJ, USA
ECHO virus: Enteric Cytopathic Human Orphan virus.
Table 4. Preclinical research progress of genetically modified HSV in the last decade—tumor suppressor genes.
Table 4. Preclinical research progress of genetically modified HSV in the last decade—tumor suppressor genes.
Target GeneNameYearApplication MethodTumor ModelROAPreclinical Outcome
PTENHSV-P10 [67] (HSV-1)20181 × 105 PFUDB7
U87ΔEGFR
i.t.Overcame tumor immune escape.
oHSV-P10 [68] (HSV-1)20232 × 105 PFUGBM-12
005 GSCs
i.t.Reduced tumor growth.
PTEN-VP22 [66] (HSV-1)2016100 μgEca-109i.t.Increased the antitumor activity of PTEN.
P53MH1004 [69] (HSV-1)20162 × 106 PFUB16-F10i.t.Reduced tumor growth, prolonged animal survival.
PTEN: phosphatase and tensin homolog deleted on chromosome ten; i.t.: intratumoral injection.
Table 5. Preclinical research progress of genetically modified HSV in the last decade—anti-angiogenic factor genes.
Table 5. Preclinical research progress of genetically modified HSV in the last decade—anti-angiogenic factor genes.
Target GeneNameYearApplication MethodTumor ModelROAPreclinical Outcome
TSP-1T-TSP-1 [16] (HSV-1)20131 × 107 PFUTMK-1, MKN1i.t.Reduced tumor angiogenesis.
AngiostatinG47Δ-mAngio [17] (HSV-1)2013G47Δ-mIL12; 1 × 106 PFUGSCs, U87i.t.Reduced tumor growth.
EndostatinHSV-Endo [19] (HSV-1)20121 × 107 PFUL1C2i.t.Reduced vascular density, incomplete regression.
VAE [18] (HSV-1)20145 × 104 PFUGBM-SCsi.t.Reduced tumor growth.
TSP-1: thrombospondin-1; i.t.: intratumoral injection.
Table 6. Preclinical research progress of genetically modified HSV in the last decade—tumor antibody-associated genes.
Table 6. Preclinical research progress of genetically modified HSV in the last decade—tumor antibody-associated genes.
Target GeneName [77,78]YearApplication MethodTumor ModelROAPreclinical Outcome
PD-1 antibodyNG34scFvPD-1 [73,74] (HSV-1)20191.5 × 106 PFUGL261, CT2Ai.t.Induced durable antitumor response.
2023PI3K inhibitor; 1 × 106 PFUID8i.t.Reduced tumor growth, prolonged animal survival.
YST-OVH [75] (HSV-1)20221 × 107 PFUHepa1-6i.t.Antitumor immunity and safe.
HSV-aPD-1 [77] (HSV-1)20211 × 107 PFUMC38, B16-F10i.t.Reduced tumor growth.
VT1903M [76] (HSV-1)20221 × 107 PFUCT26i.t.Reduced tumor growth.
oHSV2-aPD1 [78] (HSV-2)20192 × 105 PFUB16Ri.t.Induced durable antitumor response.
HER2 antibodyVG22401 [79] (HSV-1)20231 × 107 PFUCT26i.t.Enhanced antitumor immunity and efficacy.
R337 [80] (HSV-1)20211 × 107, 1.5 × 107, 5 × 107 PFUCT26-HER2i.t.Enhanced antitumor immunity.
R-335 [81] (HSV-1)20211 × 108 PFUHER2-LLC1i.t.Improved immunosuppressive microenvironment.
R-LM113 [82] (HSV-1)2020PD-1 antibody; 1 × 108 PFUHER2-LLC1i.t.Sting provides fundamental contributions to immunotherapeutic efficacy.
R87 [83] (HSV-1)20181 × 108 PFUHER2-LLC1i.t.Targeted HER2+ cancer cells.
EGFR antibodyOV-Cmab-mCCL5 [86] (HSV-1)20222 × 105 PFUCT2A-hEGFRi.t.Reduced tumor growth, prolonged animal survival.
R-613 [87] (HSV-1)20211 × 109 PFUGBMi.t.Increased animal median survival time.
Sting: stimulator of interferon genes; i.t.: intratumoral injection.
Table 7. Preclinical research progress of genetically modified HSV in the last decade—viral native genes.
Table 7. Preclinical research progress of genetically modified HSV in the last decade—viral native genes.
Target GeneMechanism of ActionNameYearApplication MethodTumor ModelROAPreclinical Outcome
gD (US6)Binds to HVEM/nectin-1, promotes membrane fusionR-LM249 [116] (HSV-1)20132 × 107, 1 × 108 PFUSK-OV-3, MDA-MB-453i.p.Reduced tumor growth, 95% reduction of neoplastic nodules.
ICP34.5 (RL1)Reduces neurotoxicity; enhances tumor infection specificityHSV1716 [97,98,99,100,101,102,103] (HSV-1)20142 × 106, 1 × 106 PFUHuH7, HepG2i.t.
i.v.
Reduced tumor growth, prolonged animal survival.
20175 × 106 PFUDIPGi.t.Inhibited brain tumor migration and invasion.
2017A8301; 1 × 108 PFURMSi.t.Prolonged animal survival, some complete responses.
2017Alisertib; 1 × 107 PFUS462TY, SK-N-ASi.t.Reduced tumor growth, prolonged animal survival.
20211 × 106 PFUPyMT-TS1, 4T1, E0771i.v.Reduced tumor growth, prolonged animal survival.
2023Bortezomib; 1 × 106 PFUJJN-3, 5TGM1i.v.Lower tumor burden rates, prevented myeloma cell regrowth.
2022BRAFi; 5 × 105 PFU4434, Mel888i.t.Enhanced survival, but cannot fully control tumors.
G207 [104,105] (HSV-1)20121 × 107 PFUHT29, PLC5i.t.Provided potential targets to overcome resistance.
20161 × 107 PFUD425, D341i.t.Pediatric medulloblastoma may be an excellent target.
ICP34.5, ICP47 (US12); GALV-GP-REnhances viral oncolytic effect, increases immunogenic cell deathVirus 16 [106] (HSV-1)2019CTLA-4 antibody; 5 × 106 PFUA20, A549, MDA-MB-231i.t.Reduced tumor growth.
ICP34.5, ICP47 (US12)VT09X [117] (HSV-1)2022Pembrolizumab; 1 × 107 PFUB16-F10i.t.Antitumor immune response, prolonged animal survival.
ICP6 (UL39), ICP47, US11Promotes viral DNA synthesis; affects MHC-I molecule expressionG47Δ [90,91,92,93,94,95,96] (HSV-1)20143 × 106 PFUMPNST, S462i.t.Reduced tumor growth, prolonged animal survival.
2017PD-1 and CTLA-4 antibody; 5 × 105 PFU005 GSCs, CT-2Ai.t.Prolonged animal survival.
2020O6-BG, TMZ; 5 × 105 PFU005 GSCsi.t.Prolonged animal survival.
20202 × 106 PFU4T1i.t.Reduced tumor burden and metastasis.
2018PD-1 and CTLA-4 antibody; 5 × 105 PFU005 GSCsi.t.Antitumor immune response.
2018Axitinib; 2.5 × 105 PFU005 GSCs, MGG123i.t.Prolonged animal survival.
20245 × 105 PFU005 GSCs, CT-2A, GL261i.t.Stimulated antitumor immunity, prolonged median survival.
VP16 (UL48)Initiates immediate-early gene transcriptionKM100 [118] (HSV-1)20162 × 107 PFUTUBOi.t.Prolonged animal survival.
gK (UL53), ICP27 (UL54)Promotes membrane fusion; affects mRNA splicingHF10 [109,110,111,112,113,114] (HSV-1)2014Erlotinib; 1 × 105 PFUBxPC3, PANC-1i.t.Combination therapy is more effective.
20211 × 107 PFUNMOC1i.t.Prolonged animal survival.
20171 × 107 PFUMC26i.t.Inhibited tumor metastasis.
2017DTIC; 1 × 107 PFUclone M3i.t.Induced anti-tumor immune response and prolonged survival.
2019Cetuximab; 5 × 106 PFUHT-29i.t.Antitumor immune response, suppressed angiogenesis.
20201.5 × 106 PFUFaDu, SCC-VIIi.t.Reduced tumor growth, prolonged animal survival.
GALV-GP-R: envelope glycoprotein of gibbon ape leukemia virus; BRAFi: BRAFV600E mutant-specific inhibitor; DTIC: dacarbazine; O6-BG: O6-Benzylguanine; TMZ: Temozolomide; i.p.: intraperitoneal injection; i.t.: intratumoral injection; i.v.: intravenous injection.
Table 8. Overview of clinical research of genetically modified HSV in the last decade—neuroectodermal tumors.
Table 8. Overview of clinical research of genetically modified HSV in the last decade—neuroectodermal tumors.
NameTargetIndicationsCombination TherapyPhase/StatusROAYearClinical Trial No.Clinical Outcome
HSV1716ICP34.5Malignant Glioma/Phase I/Terminatedi.t.2013NCT02031965Data not reported.
C134ICP34.5; HCMV-TRS1Recurrent Glioblastoma/Phase Ib/Active, not recruitingi.t.2024NCT06193174Clinical studies are ongoing.
/Phase I/Active, not recruitingi.t.2019NCT03657576
Malignant Glioma/Phase II/Active, not recruitingi.t.2024NCT06614855
G47ΔICP34.5, ICP47; LacZMalignant Glioma/Phase I-II/Completedi.t.2019UMIN000002661Median OS 23.3 months, 1-year survival rate 92.3%.
/Phase II/Completedi.t.2020UMIN000015995
rQNestin34.5v.2ICP34.5, UL39Malignant Glioma/Phase I/Recruitingi.t.2017NCT03152318Clinical studies are ongoing.
G207ICP34.5; LacZMalignant Glioma5Gy radiotherapyPhase II/Recruitingi.t.2024NCT04482933
Recurrent Brain Tumor5Gy radiotherapyPhase I/Recruitingi.t.2019NCT03911388
Phase I/Completedi.t.2020NCT02457845Median OS 23.3 months.
ON-01TK, RR, UNGMalignant Glioma/Phase I-II/Completedi.t.2022NCT06562621Data not reported.
MVR-C5252ICP34.5; IL-12, PD-1Malignant Glioma/Phase I/Recruitingi.t.2024cClinical studies are ongoing.
M032ICP34.5; IL-12Recurrent Malignant Glioma/Phase I/Active, not recruitingi.t.2022NCT02062827Data not reported.
PembrolizumabPhase I-II/Recruitingi.t.2022NCT05084430Clinical studies are ongoing.
OH2GM-CSFRecurrent Glioblastoma/Phase I-II/Recruitingi.t.2021NCT05235074
HCMV-TRS1: Human Cytomegalovirus-TRS1; LacZ: β-galactosidase gene; TK: thymidine kinase; RR: ribonucleotide reductase; UNG: uracil DNA glycosylase; OS: overall survival; i.t.: intratumoral injection.
Table 9. Overview of clinical research of genetically modified HSV in the last decade—skin and soft tissue sarcomas.
Table 9. Overview of clinical research of genetically modified HSV in the last decade—skin and soft tissue sarcomas.
NameTargetIndicationsCombination TherapyPhase/StatusROAYearClinical Trial No.Clinical Outcome
T-VECGM-CSFMelanoma/Phase III/Completedi.t.2014NCT00769704ORR 31.5%, median OS 23.3 months, DRR 19%.
EBRTPhase II/Completedi.t.2016NCT028198430% grade 3 AEs.
IpilimumabPhase II/Completedi.t.2021NCT01740297ORR 35.7%, median PFS 13.5 months.
NivolumabPhase II/Completedi.t.2020NCT04330430Pathologic CR 45%.
PembrolizumabPhase II/Recruitingi.t.2019NCT03842943Clinical studies are ongoing.
Advanced Soft Tissue SarcomaEBRTPhase I/Recruitingi.t.2024NCT06660810
NivolumabPhase II/Recruitingi.t.2019NCT03886311
Non-melanoma Skin Cancer/Phase I/Completedi.t.2022NCT03458117Data not reported.
ONCR-177IL-12, CCL4, FLT3LG, PD-1 and CTLA-4 antibodiesSkin/Subcutaneous MalignanciesPembrolizumabPhase I/Terminatedi.t.2020NCT04348916Data not reported.
OrienX010GM-CSFMalignant Melanoma/Phase I/Unknowni.t.2016NCT03048253Data not reported.
Melanoma/Phase I/Completedi.t.2012NCT01935453
T3011IL-12, PD-1 antibodyNon-melanoma Skin Cancer, Sarcoma/Phase I-II/Unknowni.t.2020NCT05602792Results unknown.
RP1GM-CSF, GALV-GP R-Melanoma/Phase I/Recruitingi.t.2024NCT06216938Clinical studies are ongoing.
Squamous Cell Carcinoma/Phase I-II/Recruitingi.t.2023NCT05858229
Advanced Skin Malignancies/Phase I-II/Recruitingi.t.2020NCT04349436
Non-melanoma Skin CancerNivolumabPhase II/Recruitingi.t.2017NCT03767348
RP2GM-CSF, GALV-GP R-, CTLA-4 antibodyMetastatic Uveal MelanomaNivolumabPhase II-III/Recruitingi.t.2024NCT06581406Clinical studies are ongoing.
HF10UL43, UL49.5, UL55, UL56, LATMelanomaNivolumabPhase II/Completedi.t.2018NCT03259425ORR 83.3%, 14.3% grade 3 AEs.
IpilimumabPhase II/Completedi.t.2018NCT03153085Data not reported.
2016NCT02272855
/Phase I/Completedi.t.2015NCT01017185
OH2GM-CSFMelanomaPembrolizumabPhase I-II/Recruitingi.t.2018NCT04386967Clinical studies are ongoing.
PD-1 antibody HX008Phase I-II/Recruitingi.t.2020NCT04616443
/Phase III/Recruitingi.t.2023NCT05868707
Soft Tissue SarcomaPD-1 antibody HX008Phase I-II/Recruitingi.t.2019NCT03866525
R130CD3 scFv, CD86, PD-1, HSV2-US11Melanoma/Phase I/Recruitingi.t.2023NCT05961111
NCT06171282
Clinical studies are ongoing.
Advanced Bone/Soft Tissue Tumors/Phase I/Recruitingi.t.2023
NCT05851456
Sarcoma/Phase I/Recruitingi.t.2023NCT05860374
KB707IL-2, IL-12Melanoma/Phase I-II/Recruitingi.t.2023NCT05970497
HSV1716ICP34.5Sarcoma/Phase I/Completedi.t.2018NCT00931931Data not reported.
EBRT: External Beam Radiation Therapy; FLT3LG: FMS-like Tyrosine Kinase-3 Ligand; LAT: Latency-associated Transcripts; ORR: objective response rate; OS: overall survival; DRR: durable response rate; AE: adverse event rates; PFS: progression-free survival; CR: complete response; i.t.: intratumoral injection.
Table 10. Overview of clinical research of genetically modified HSV in the last decade—mucosal epithelial tumors.
Table 10. Overview of clinical research of genetically modified HSV in the last decade—mucosal epithelial tumors.
IndicationsNameTargetCombination TherapyPhase/StatusROAYearClinical Trial No.Clinical Outcome
Respiratory System
Head and Neck CancerT3011IL-12, PD-1 antibody/Phase I–II/Unknowni.t.2020NCT05602792Results unknown.
T-VECGM-CSFPembrolizumabPhase I/Completedi.t.2017NCT02626000Median PFS 3.0 months, OS 5.8 months.
HF10UL43, UL49.5, UL55, UL56, LAT/Phase I/Completedi.t.2015NCT01017185Data not reported.
OH2GM-CSFPD-1 antibody HX008Phase I–II/Recruitingi.t.2019NCT03866525Clinical studies are ongoing.
R130CD3 scFv, CD86, PD-1, HSV2-US11/Phase I/Recruitingi.t.2023NCT05961111
/Phase I/Unknowni.t.2023NCT05886075Results unknown.
/Phase I/Recruitingi.t.2023NCT05830240Clinical studies are ongoing.
Lung CancerOrienX010GM-CSF/Phase I/Completedi.t.2012NCT01935453Data not reported.
T3011IL-12, PD-1 antibody/Phase I–II/Unknowni.v.2022NCT05598268Results unknown.
RP2GM-CSF, GALV-GP R-, CTLA-4 antibodyNivolumabPhase I/Recruitingi.t.2019NCT04336241Clinical studies are ongoing.
R130CD3 scFv, CD86, PD-1, HSV2-US11/Phase I/Recruitingi.t.2023NCT05961111
/Phase I/Unknowni.t.2023NCT05886075Results unknown.
KB707IL-2, IL-12/Phase I–II/Recruitingnebulization2024NCT06228326Clinical studies are ongoing.
Pleural MesotheliomaHSV1716ICP34.5/Phase I–II/Completedi.p.2016NCT01721018Data not reported.
Digestive System
Gastric CancerVG161IL-12, IL-15, PD-L1BNivolumabPhase I–II/Recruitingi.t.2022NCT06008925Clinical studies are ongoing.
OH2GM-CSFPD-1 antibody HX008Phase I–II/Recruitingi.t.2019NCT03866525
Liver CancerOrienX010GM-CSF/Phase I/Completedi.t.2012NCT01935453Data not reported.
T3011IL-12 and PD-1 antibody/Phase I–II/Unknowni.v.2022NCT05598268Results unknown.
T-VECGM-CSF/Phase I/Completedi.t.2018NCT03256344ORR 10%, PFS 5.4 months, OS 19.2 months.
RP2GM-CSF, GALV-GP R-, CTLA-4 antibodyNivolumabPhase I/Recruitingi.t.2019NCT04336241Clinical studies are ongoing.
Atezolizumab and BevacizumabPhase II/Recruitingi.t.2024NCT05733598
VG161IL-12, IL-15, PD-L1BCamrelizumabPhase I-II/Not yet recruitingi.t.2023NCT06124001
/Phase I/Recruitingi.t.2021NCT04806464
R130CD3 scFv, CD86, PD-1, HSV2-US11/Phase I/Recruitingi.t.2023NCT05860374
Pancreatic CancerOrienX010GM-CSF/Phase I/Completedi.t.2012NCT01935453Data not reported.
HF10UL43, UL49.5, UL55, UL56, LATGemcitabine + PaclitaxelPhase I/Active, not recruitingi.t.2020NCT03252808Clinical studies are ongoing.
Erlotinib + GemcitabinePhase I/Completedi.t.2018UMIN000010150Median PFS 6.3 months, median OS 15.5 months.
T-VECGM-CSF/Phase I/Completedi.t.2017NCT03086642Median OS 7.8 months.
VG161IL-12, IL-15, PD-L1BNivolumabPhase I-II/Recruitingi.t.2022NCT05162118Clinical studies are ongoing.
OH2GM-CSF/Phase I-II/Terminatedi.t.2021NCT04637698Results unknown.
Colorectal CancerONCR-177IL-12, CCL4, FLT3LG, PD-1 and CTLA-4 antibodyPembrolizumabPhase I/Terminatedi.t.2020NCT04348916Results unknown.
T3011IL-12 and PD-1 antibodyToripalimab + RegorafenibPhase I/Recruitingi.v.2024NCT06283303Clinical studies are ongoing.
RegorafenibPhase I/Recruitingi.v.2023NCT06200363
R130CD3 scFv, CD86, PD-1, HSV2-US11/Phase I/Recruitingi.t.2023NCT05860374
Urogenital System
Bladder CancerT3011IL-12 and PD-1 antibody/Phase I/Recruitingbid.2023NCT06427291Clinical studies are ongoing.
OH2GM-CSF/Phase I-II/Recruitingbid.2022NCT05232136
/Phase II/Recruitingi.t.2022NCT05248789
Ovarian CancerR130CD3 scFv, CD86, PD-1, HSV2-US11/Phase I/Recruitingi.t. or i.v.2022NCT05801783
Cervical Cancer/Phase I/Recruitingi.t. or i.v.2023NCT05812677
BS-006CD3 and PD-L1 antibod/Phase I/Recruitingi.t.2022NCT05393440
i.t.: intratumoral injection; i.v.: intravenous injection; i.p.: intraperitoneal injection; bid.: bladder instillation drip; PFS: progression-free survival; OS: overall survival; ORR: objective response rate.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zheng, Y.; Pei, Y.; Dong, C.; Liang, J.; Cai, T.; Zhang, Y.; Tan, D.; Wang, J.; He, Q. Oncolytic Herpes Simplex Virus Therapy: Latest Advances, Core Challenges, and Future Outlook. Vaccines 2025, 13, 880. https://doi.org/10.3390/vaccines13080880

AMA Style

Zheng Y, Pei Y, Dong C, Liang J, Cai T, Zhang Y, Tan D, Wang J, He Q. Oncolytic Herpes Simplex Virus Therapy: Latest Advances, Core Challenges, and Future Outlook. Vaccines. 2025; 13(8):880. https://doi.org/10.3390/vaccines13080880

Chicago/Turabian Style

Zheng, Yiyang, Yusheng Pei, Chunyan Dong, Jinghui Liang, Tong Cai, Yuan Zhang, Dejiang Tan, Junzhi Wang, and Qing He. 2025. "Oncolytic Herpes Simplex Virus Therapy: Latest Advances, Core Challenges, and Future Outlook" Vaccines 13, no. 8: 880. https://doi.org/10.3390/vaccines13080880

APA Style

Zheng, Y., Pei, Y., Dong, C., Liang, J., Cai, T., Zhang, Y., Tan, D., Wang, J., & He, Q. (2025). Oncolytic Herpes Simplex Virus Therapy: Latest Advances, Core Challenges, and Future Outlook. Vaccines, 13(8), 880. https://doi.org/10.3390/vaccines13080880

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop