Infecting Cancer to Cure It: The Power of Oncolytic Viruses in Gynecologic Oncology – A Narrative Review

Keywords

adenovirus - cervical cancer - endometrial cancer - oncolytic virotherapy - ovarian cancer - virus

Introduction

Gynecologic malignancies, such as ovarian, cervical, and endometrial cancers, pose significant threats to women’s health worldwide and account for a substantial portion of the global cancer burden [1]. Recent data from 2022 reveals that gynecological cancers were responsible for approximately 1,473,427 new cases and 680,372 deaths worldwide [2]. Despite advancements in the management of gynecological cancers, significant challenges remain, highlighting the urgent need for innovative and targeted treatment approaches [3].

Oncolytic viruses (OVs) have gained significant attention in the twenty-first century due to their unique ability to induce direct tumor cell destruction (oncolysis) and modulate the immune system against cancer. As a cutting-edge therapeutic strategy, oncolytic virotherapy (OVT) leverages the selective replication of these viruses in tumor cells, effectively eliminating malignant cells while sparing healthy tissues [4] [5].

Methodology

This narrative review was conducted to evaluate the current state and future prospects of OVT in the management of gynecological cancers. A comprehensive literature search was performed using PubMed, Scopus, and Web of Science databases, focusing on studies published between December 2005 and December 2024. Keywords used included “oncolytic virotherapy,” “gynecological cancers,” “ovarian cancer,” “cervical cancer,” “endometrial cancer,” “oncolytic viruses,” and specific virus types like “adenovirus,” “herpes simplex virus,” and “Newcastle disease virus.” Inclusion criteria encompassed preclinical and clinical studies assessing the efficacy, safety, and mechanisms of OVT in gynecological malignancies. Articles discussing combinatorial approaches involving OVs and other therapies, such as chemotherapy, radiotherapy, or immune checkpoint inhibitors, were also included. Exclusion criteria involved non-English publications, studies lacking experimental or clinical data, and those focusing solely on non-gynecological cancers. Data extraction emphasized the types of OVs, therapeutic outcomes, immune modulation effects, tumor microenvironment (TME) changes, and advancements in OV engineering, focusing on studies reporting clinical efficacy. The present review explores the transformative potential of OVT in gynecological cancers, providing comprehensive insights into its therapeutic role.

Oncolytic Viruses: Types and Mechanisms of Action

OVs are classified based on their nucleic acid type into single- or double-stranded RNA or DNA viruses. The most common types include double-stranded (ds) DNA viruses such as adenovirus, vaccinia virus, and herpesvirus, and single-stranded (ss) RNA viruses, which are further categorized into positive-sense (e. g., coxsackievirus, Seneca Valley virus, poliovirus) and negative-sense (e. g., measles virus, Newcastle disease virus, vesicular stomatitis virus). Positive-sense ssRNA viruses can directly translate their genetic material into proteins, while negative-sense ssRNA viruses require transcription into complementary RNA before translation. OVs are also classified as naturally attenuated strains or genetically engineered viral vectors based on their structure [4].

OVT has evolved across four generations. The first generation focused on genome modifications to enhance tumor cell specificity while minimizing damage to normal tissues. The second generation introduced OVs armed with viral and non-viral genes. The third generation incorporated multiple coordinated genes to enhance tumor immunotherapy. The fourth generation advanced further by engineering OVs to activate T cells, including the use of bi-specific T cell activators (BiTA) to bolster the immune response [6] [7].

Mechanisms of Oncolytic Virus-Induced Tumor Destruction

Oncolytic viruses (OVs) utilize the following mechanisms to achieve tumor cell destruction:

Enhances cell death

Viral infections influence cell death through death receptor-mediated pathways, where receptors like Fas, tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R), and tumor necrosis factor receptor (TNF-R) form death-inducing signaling complexes to trigger apoptosis. Viruses activate the caspase cascade by regulating the interaction between death receptors and their ligands (including viral proteins), initiating extrinsic apoptosis. This mechanism facilitates efficient cell death and aids in viral progeny dissemination [8] [9]. Another mechanism by which OVs induce cell death is necroptosis, a programmed form of cell death that mimics necrosis in morphology [10]. Necroptosis involves plasma membrane rupture, organelle swelling, leakage of intracellular contents, and eventual cell death. Unlike uncontrolled necrosis, necroptosis is a regulated process and is recognized as a common pathway of OV-induced tumor cell elimination [9] [11] [12]. OVs can also induce cell death through pyroptosis, a highly inflammatory form of programmed cell death [13] [14]. Pyroptosis is characterized by the formation of pores in the cell membrane, leading to membrane rupture, cell lysis, and death [15]. This process not only contributes to tumor reduction but also triggers robust antitumor immune responses. During pyroptosis, proinflammatory cytokines like Interleukin (IL)-1β and IL-18, along with damage-associated molecular patterns, are released, serving as adjuvants to activate and enhance the immune system’s attack on the tumor [9].

Immune-mediated action

The primary mechanism of OVs is immune-mediated oncolysis. Effective tumor eradication with OVs primarily depends on activating systemic innate immunity and tumor-specific adaptive immune responses [16]. Immunovirotherapy is an advanced therapeutic approach that harnesses viruses to specifically target and destroy tumor cells while simultaneously activating the immune system to mount a robust anti-tumor response [17] [18].

Cancer cells develop strategies to suppress antitumor immunity, creating a non-immunogenic (“cold”) TME with minimal T-cell infiltration and low mutational burden. OVs can transform these "cold" tumors into immunogenic (“hot”) ones by promoting tumor antigen release from dying cancer cells, boosting T-cell infiltration, and triggering robust antitumor immune responses [19] [20] [21] [22]. Tumor cell lysis releases viral progeny along with tumor-associated antigens (TAAs), pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs), triggering tumor immunogenic cell death (ICD). PAMPs and DAMPs activate innate immunity by binding to receptors like Toll-like receptors (TLRs), while mature dendritic cells (DCs) and natural killer (NK) cells are stimulated to enhance OV-driven tumor clearance [9] [23]. Moreover, OVs, either independently or as therapeutic platforms, can enhance the production of inflammatory cytokines (e. g., IL-2, IL-12, IL-15, TNF-α) [20] and chemokines (e. g., CXCL9, CXCL10, CXCL11) within the TME [24]. This immune activation promotes T-cell migration and infiltration, amplifying the antitumor immune response [9]. Hence, OVs are inherently able to transform immunologically cold tumors into hot, immune-responsive ones by promoting immune cell and cytokine infiltration. This effect can be further amplified by engineering OVs with transgenes that enhance their immunostimulatory properties, directing immune responses specifically toward cancer cells for more targeted and potent antitumor activity [25]. OVs can be engineered to deliver immunostimulatory molecules directly into the tumor, such as tumor antigens or cytokines, further amplifying the antitumor immune response. Furthermore, OVs can be strategically combined with other cancer immunotherapies, including immune checkpoint inhibitors (ICI), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs), and autologous tumor-infiltrating lymphocytes (TILs), to create a synergistic effect that enhances tumor targeting and improves overall therapeutic outcomes [26] [27] [28] [29]. Bi- and tri-specific antibodies that target tumor antigens and activate T-cell receptor signaling have emerged as promising tools in cancer immunotherapy. A novel approach combines these antibodies with OVs, creating BiTE- or TriTE-armed OVs for targeted immunotherapy. BiTEs are bispecific proteins consisting of two single-chain variable fragments (scFvs), one targeting a TAA and the other binding to T-cell molecule CD3. TriTEs expand this design by adding a third binding site, such as CD28, further enhancing T-cell activation and anti-tumor response while bypassing the need for antigen presentation by Antigen-presenting cells [30] [31].

Anti-angiogenic action

OVs can be engineered to target tumor vasculature or endothelial cell receptors specifically. Their action disrupts intratumoral blood flow by recruiting neutrophils and inducing vascular collapse. This process results in fibrin deposition and thrombosis, ultimately contributing to tumor destruction through the shutdown of its blood supply [4] [32] [33]. Furthermore, OVs compromise tumor vasculature by targeting tumor-associated endothelial cells and nearby tumor cells, inducing an inflammatory cascade that releases TNF-α and Interferon (IFN)-γ [16].

Other mechanisms

The extracellular matrix (ECM) serves as a critical growth niche for most solid tumors, forming a physical barrier that contributes to cancer initiation, progression, metastasis, and drug resistance [34] [35]. OVs effectively disrupt this structural barrier, bridging the gap between non-infiltrated immune cells and the TME. Administered intratumorally, OVs propagate autonomously, bypassing the need for vascular delivery and enhancing drug delivery efficiency. By encoding modifiers of ECM-related molecules, OVs induce significant alterations in the TME, triggering the release of inflammatory mediators and cytotoxic proteases that degrade the ECM and facilitate immune cell infiltration [4] [33] [36].

[Fig. 1] depicts the mechanism of action of oncolytic viruses.

Fig. 1 Mechanism of action of Oncolytic Viruses.

Delivery Routes of OVs

OVs can be delivered through multiple routes, including intravenous, intratumoral, intrapleural, intraperitoneal, aerosolized, and limb injections [6].

• Direct Intratumoral Route: Intratumoral injection remains the most commonly used method for delivering oncolytic viruses, offering precise control over viral concentration at the tumor site while minimizing off-target effects in healthy tissues. This localized approach ensures sustained exposure of the tumor to the virus, enhancing therapeutic efficacy [37] [38]. However, its application is largely limited to accessible or superficial tumors, making it unsuitable for deep-seated or multifocal malignancies such as those in the brain or pancreas. Additionally, effective intratumoral delivery requires the presence of viable tumor cells to support viral replication and immune activation. Accurate tumor localization and identification of optimal injection sites are, therefore, critical to maximize treatment benefits [38] [39].

• Intravenous route: Intravenous administration of oncolytic viruses offers a more easy, straightforward, and less invasive route of delivery [37]. This delivery route is particularly advantageous for treating metastatic disease, as it enables oncolytic viruses to circulate systemically and reach multiple tumor sites throughout the body [38]. A recent phase III clinical trial demonstrated that intravenous infusion of paclitaxel in combination with oncolytic reovirus yielded promising therapeutic outcomes in patients with recurrent ovarian, fallopian tube, and primary peritoneal cancers [40]. Additionally, emerging research has investigated the potential of enhancing intravenously delivered oncolytic virus vaccines by incorporating functional peptides, aiming to improve their tumor-targeting specificity and therapeutic efficacy [41]. Theoretically, systemic or intravenous delivery represents an optimal strategy, as it allows widespread distribution of oncolytic viruses, enabling them to target both primary tumors and distant metastases and is amenable to repeated dosing. However, a major limitation is the rapid clearance of viral particles by the host immune system, and poor penetration into tumors [42]. Furthermore, this strategy often requires the administration of high viral titers to ensure adequate distribution and therapeutic efficacy, which may increase the risk of off-target effects, including toxicity and unintended infection of healthy tissues [38] [43]. To overcome this challenge, recent advances have explored the use of synthetic nanoparticle coatings to shield oncolytic viruses, thereby enhancing their circulation time and reducing neutralization by antiviral antibodies [39].

• Intraperitoneal Route: Given the expansive surface area of the peritoneum, drugs delivered via intraperitoneal injection are rapidly absorbed, making this route particularly effective for targeting intra-abdominal organs [37]. Intraperitoneal administration of oncolytic viruses offers a promising strategy to directly reach peritoneal tumors, providing localized therapeutic delivery to manage peritoneal metastases more efficiently [38]. In a preclinical study, the combination of the oncolytic virus JX-594 with immune checkpoint inhibitors (ICIs), administered intraperitoneally, demonstrated significant therapeutic potential. This approach not only reversed the immunosuppressive environment within the peritoneal cavity but also amplified the efficacy of immune checkpoint blockade against colon cancer, resulting in substantial suppression of peritoneal carcinomatosis and malignant ascites [38] [44].

• Other routes: Other less frequently utilized delivery routes for oncolytic viruses include subcutaneous, intrathecal, intrapleural, oral, and limb injections, primarily due to their limited efficiency and narrow therapeutic scope. While subcutaneous injection is commonly employed in small animal models, particularly when intravenous access is challenging, it has limited clinical applicability [37] [45]. Intrathecal and intrapleural routes, meanwhile, are confined to specific anatomical regions, with intrathecal injections targeting central nervous system malignancies and intrapleural injections being applicable primarily to thoracic tumors such as those in the lungs or pleura [37]. Furthermore, aerosolized and intranasal delivery of oncolytic viruses are emerging as innovative approaches for cancer therapy, particularly in the treatment of pulmonary malignancies such as lung cancer [46].

Exploring the Efficacy of OVT in Gynecologic Cancer Therapy

OVT is emerging as a pivotal approach in managing gynecological malignancies, demonstrating encouraging clinical outcomes. Various OVs are employed in treating these cancers as standalone therapies or in synergy with other treatment modalities [47] [48]. Moreover, integrating OVs with other therapies significantly improves cancer treatment outcomes. These viruses trigger localized tumor inflammation, enhancing immune responses and amplifying the effects of immunotherapy. This strategy helps the immune system identify and destroy cancer cells while counteracting the tumor’s immune evasion tactics [16]. Studies have demonstrated that combining oncolytic vaccinia virus (VV) therapy with conventional cancer treatments yields a synergistic effect, proving more effective than standalone therapies [49] [50].

Role of OVT in the Management of Ovarian Cancer

OVs present a highly promising strategy for the treatment of ovarian cancer, especially for therapy-resistant ovarian cancers [51]. Despite debulking surgery and chemotherapy treatment strategy, most patients experience relapse and develop drug-resistant metastatic disease, often driven by cancer stem cells (CSCs) or cancer-initiating cells (CICs). OVs offer a promising alternative by bypassing traditional drug-resistance mechanisms, potentially providing a safe and effective therapy for chemotherapy-resistant CSCs/CICs. Furthermore, Antibodies against immune checkpoint proteins like anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death protein-1 (PD-1) have been approved for ovarian cancer treatment, showing durable clinical benefits. However, their efficacy often depends on a pre-existing active immune TME. Integrating oncolytic therapies with checkpoint inhibitors provides a synergistic strategy, boosting tumor-specific immune responses while counteracting immune suppression, thereby enhancing overall therapeutic outcomes [52].

Adenoviruses and vesicular stomatitis virus (VSV) are among the most widely studied and commonly employed vectors in virotherapy for ovarian cancers for their ability to preferentially replicate in cancer cells and induce oncolysis [53] [54]. The role of various OVs in managing advanced ovarian cancer is explored in the following studies:

1. Adenovirus: A study showed that two ovarian oncolytic adenoviruses, OvAd1, developed using Matrigel cultures, and OvAd2, from traditional monolayers, effectively target platinum-resistant ovarian cancer cell lines while sparing normal cells, offering a 200-fold therapeutic window. Unlike adenovirus-5 (Ad5)-based therapies, neither virus caused peritoneal adhesions, making OvAd1 and OvAd2 promising candidates for treating aggressive ovarian cancer [55]. In another study, Ad-5 was engineered into Ad5NULL-A20, a tumor-selective virotherapy designed to target αvβ6 integrin, a marker overexpressed in aggressive epithelial ovarian cancers. This advanced vector enables precise local and systemic targeting of αvβ6-positive tumors, offering a versatile platform for delivering tumor-specific anticancer therapies, including ICIs [56]. A study explored the impact of oncolytic adenovirus on malignant ascites in a mouse model with advanced ovarian cancer. OV effectively reduced ascites formation and extended overall survival. Immune profiling revealed that OV treatment enhanced T cell infiltration, activation, and effector differentiation, reprogrammed macrophages to an M1-like phenotype, and improved CD8+/CD4+T cell and M1/M2 macrophage ratios. It was observed that combining OV with the colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX3397 and anti-PD1 therapy significantly delayed ascites progression, further amplifying T cell infiltration, activation, and proliferation [57]. A recent study engineered an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), armed with a human aMUC1aCD3 T-cell engager and interleukin-2 (IL-2), and evaluated its efficacy on ascites samples derived from ovarian cancer patients with peritoneal carcinomatosis. This treatment enhanced T cell cytotoxicity, increasing granzyme B, perforin, and IFN-γ levels. Immune profiling showed that TILT-322 also activated gamma delta T cells and impacted NK and NK-like T cells. Moreover, it reduced the proportion of exhausted CD8+T cells in ovarian ascites. Hence, TILT-322 shows great promise as a novel anti-tumor agent for clinical use [58]. A similar study utilizing the oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 (TILT-123) to deliver TNF-α and IL-2 demonstrated its potential to overcome immunosuppression and boost antitumor T cell infiltrates (TILs) in ovarian cancer. The treatment reprogrammed the TME to enhance TIL reactivity, potentially improving the clinical outcomes of adoptive TIL therapy in patients with advanced ovarian cancer [59]. Furthermore, A novel oncolytic adenovirus, AR2011, was developed to target ovarian tumors and demonstrated potent lytic effects in vitro on human ovarian cancer cell lines and ascitic fluid-derived malignant cells. When preloaded into menstrual blood stem cells (MenSCs), AR2011’s activity was enhanced, overcoming the inhibitory effects of ascitic fluids. MenSC-AR treatment in nude mice with peritoneal carcinomatosis effectively inhibited tumor growth, showing that MenSCs can amplify the oncolytic effects of AR2011. This strategy offers a promising approach to overcoming viral treatment barriers in ovarian cancer [60]. A study evaluating the efficacy of Enadenotucirev, a tumor-selective and blood-stable adenoviral vector, in recurrent platinum-resistant ovarian cancer, reported promising results. Administering enadenotucirev intravenously in combination with paclitaxel showed manageable tolerability, an encouraging median progression-free survival (PFS), and enhanced immune-cell infiltration within tumors, highlighting its potential as a therapeutic option for platinum-resistant ovarian cancer [61]. A similar study demonstrated that intravenous administration of enadenotucirev combined with nivolumab showed manageable tolerability, improved overall survival, and induced immune cell infiltration and activation in patients with advanced or metastatic epithelial ovarian cancer, suggesting its potential as a promising treatment approach [62].

2. Vesicular stomatitis virus (VSV): A study evaluated the oncolytic VSV in patient-derived ovarian cancer cell lines across all epithelial subtypes. The findings revealed that combining VSV with Janus kinase (JAK) inhibitors, such as ruxolitinib, significantly enhanced therapeutic efficacy. These results suggest that VSV, either alone or in combination with JAK inhibitors, holds promise as a potent treatment option for ovarian cancer [63]. A similar study revealed that in metastatic breast and ovarian cancer models, combining oncolytic VSV or reovirus with NK-T cell activation via DCs loaded with α-galactosylceramide significantly reduced tumor burden. This synergistic approach enhanced survival and decreased metastases more effectively than either treatment alone, highlighting its potential as a powerful therapeutic strategy [64].

3. Herpes simplex virus: A study evaluated an oncolytic herpes simplex virus (oHSV) armed with murine IL-12, demonstrating its efficacy against ovarian cancer cell lines in vitro. Mice treated with the IL-12-expressing oHSV showed enhanced tumor antigen-specific CD8+T-cell responses in the omentum and peritoneal cavity, resulting in better control of ovarian cancer metastases and improved survival. These findings underscore the potential of IL-12-expressing oHSV to reduce metastasis and improve outcomes in ovarian cancer [65].

4. Poxvirus: A study revealed that CF17, a chimeric poxvirus created from nine orthopoxvirus species, has enhanced oncolytic properties. In ovarian cancer, CF17 replicated and induced cytotoxicity in human and mouse cell lines. It also demonstrated strong antitumor effects in a syngeneic ovarian cancer mouse model at doses as low as 6×10⁶ plaque-forming units. These findings suggest CF17’s potential as a promising treatment for aggressive ovarian cancer [66]. A similar study explored the immunotherapeutic potential of Parapoxvirus ovis (OrfV) using the ID8 orthotopic mouse model of advanced epithelial ovarian carcinoma. The findings demonstrated that OrfV effectively reduced tumor progression as a monotherapy in an advanced-stage cancer model. The antitumor effects of OrfV were heavily reliant on NK cells, as their depletion eliminated CD8+T-cell-mediated responses against the tumor. These results highlight OrfV as a promising NK cell-stimulating immunotherapy for the treatment of advanced epithelial ovarian cancer [67]. Another recent study on the OrfV highlighted its dual role as an oncolytic agent and immune modulator. In a preclinical advanced epithelial ovarian cancer model, OrfV enhanced immune cell infiltration into the ascites TME, boosting activation markers and effector cytokines. This immune activation correlated with reduced tumor burden and prolonged survival, underscoring its potential as a multifaceted therapy for advanced-stage ovarian cancer [68]. A study evaluating intraperitoneal olvimulogene nanivacirepvec (Olvi-Vec), a modified vaccinia virus in patients with platinum-resistant or refractory ovarian cancer (PRROC) demonstrated encouraging results. The treatment showcased a favorable safety profile, notable clinical activity, and robust immune activation, highlighting its potential as a therapeutic option for managing PRROC [69]. A related trial investigated the efficacy and safety of intraperitoneal Olvi-Vec virotherapy in combination with platinum-based chemotherapy, with or without bevacizumab, in patients with PRROC. The findings revealed that Olvi-Vec, followed by immunochemotherapy, achieved encouraging objective response rates and PFS while maintaining a manageable safety profile, offering a potential therapeutic strategy for PRROC patients [70].

5. Sindbis virus: The Sindbis virus-based vaccine platform has emerged as a promising immunotherapy candidate for managing ovarian cancer. Armed oncolytic Sindbis virus (SV) vectors have demonstrated unique and compelling properties in vivo, sparking considerable interest in their potential applications in recent years [71]. A recent study highlighted the potential of the SV vector platform, specifically SVIL-12, combined with an agonistic OX40 antibody, in eradicating ovarian cancer in a Mouse Ovarian Surface Epithelial Cell model. Remarkably, this combination also prevented tumor recurrence in mice rechallenged with tumor cells after approximately five months. Additionally, engineering a single SV vector, SV.IgGOX40.IL-12, to co-express IL-12 and anti-OX40 enabled precise local delivery of immunomodulatory agents to tumors, significantly enhancing the antitumor immune response [72].

6. Maraba virus: A study demonstrated that a prime-boost strategy combining a vaccine with antigen-armed oncolytic Maraba virus elicited strong tumor-specific CD8+T cell responses, improving tumor control in ovarian cancer. While adaptive resistance led to T cell suppression in the TME, adding PD-1 blockade restored T cell function and enhanced outcomes [73].

Hence, OVs show immense potential as a therapeutic strategy for managing ovarian cancers, with ongoing research continuously uncovering new possibilities.

Role of OVT in the Management of Cervical Cancer

OVs have shown promise in the management of advanced stages of cervical cancer, acting as potent biological agents that selectively infect and destroy cancer cells while sparing healthy tissues [74]. In cervical cancer OVT, the primary viruses utilized include adenoviruses, herpes simplex viruses, parvoviruses, and Newcastle disease virus [74]. The role of various OVs in managing advanced cervical cancer is explored in the following studies:

1. Adenovirus: The genetically engineered oncolytic adenovirus CRAd AdCB016-mp53(268 N) demonstrated remarkable specificity in targeting Human papillomavirus (HPV)-positive cells by combining selective replication in HPV E6/E7-expressing cells with a p53 variant resistant to E6-mediated degradation. This virus exhibited 10- to 1000-fold greater efficacy in HPV-positive cervical cancer and dysplastic cell lines while sparing healthy keratinocytes, underscoring its precision and significant therapeutic potential [75]. Another study introduced the novel recombinant adenovirus M5, designed for tumor-specific replication and targeted expression of the HPV16 E2 gene. This virus effectively silenced HPV E6 and E7 oncogenes in cervical cancer cells, demonstrating strong antitumor activity both in vitro and in vivo. Its therapeutic potency was significantly enhanced when combined with radiation therapy [76]. A similar study on the E1A-mutant adenovirus (M6) with antisense HPV16 E6/E7 DNA showed selective replication in HPV16-positive cervical cancer cells, suppressing E6/E7 expression, inducing apoptosis, and reducing invasiveness. Combined with radiotherapy, M6 enhanced tumor inhibition, increased apoptosis, and significantly improved survival in tumor-bearing mice compared to monotherapy or Adv5/dE1A with radiation [77]. Recently it was reported that oncolytic adenoviruses effectively infect and lyse cervical cancer cells, triggering tumor cell disruption and immune activation. These viruses can deliver tumor suppressor genes like p53 and Rb, restoring their normal function in cancer cells. Adenoviruses targeting E6 and E7 oncoproteins enhance immune responses, particularly activating cytotoxic T lymphocytes (CTLs). Additionally, the integration of antisense RNAs and microRNAs (miRNAs) into adenoviral vectors specifically inhibits HPV E6 and E7 expression, effectively suppressing these oncoproteins in cervical cancer cells [78]. Another study investigated the use of adenovirus types 26 and 35 vectors expressing HPV16 E6 and E7 oncoproteins in mice through intramuscular priming followed by intravaginal (Ivag) boosting. This combined immunization strategy significantly enhanced HPV-specific CD8+T cell responses, evidenced by increased production of IFN-γ and TNF-α, along with upregulation of CD69 and CD103, markers of tissue-resident memory cells. Additionally, it induced circulating HPV-specific CD8+T cells, highlighting the potential of Ivag immunization with adenoviral vectors as a promising therapeutic approach for HPV infections and cervical intraepithelial neoplasia [79].

2. Herpes simplex virus (HSV): A recent study highlighted that therapy with a triple-mutated oncolytic HSV (T-01) significantly enhances tumor immunogenicity and boosts the efficacy of ICIs in treating HPV-associated cervical cancer [80]. A related study investigated the use of a triple-mutated oncolytic HSV (T-01) for treating HPV-associated cervical cancer. The findings revealed that T-01 exhibited potent cytotoxicity across all tested cell lines. In both the HeLa xenograft and TC-1 syngeneic mouse models, T-01 significantly suppressed tumor growth. Additionally, tumor-bearing mice treated with T-01 demonstrated a marked increase in CD8+T-cell precursors compared to control mice, highlighting the therapeutic potential of T-01 for HPV-related cervical cancer [81]. A recent study introduced SONC103, a recombinant oncolytic HSV-1 armed with CRISPR/Cas9, to disrupt integrated HPV16 genes in cervical cancer cells. SONC103 effectively knocked down HPV16 oncogenes, reducing cell proliferation and inducing apoptosis. It eliminated HPV16 DNA probes from chromosomes, downregulated E6/E7 oncoproteins, and upregulated tumor suppressor proteins p53 and pRB. In a murine cervical cancer model, SONC103 significantly inhibited tumor growth, highlighting its potential as a targeted therapy for HPV16-positive cervical cancer [82].

3. Newcastle disease virus (NDV): A study investigated the Hitchner B1 (HB1) strain of NDV as an oncolytic agent for cervical cancer. The findings showed that HB1 NDV infection significantly reduced TC-1 cell viability in a dose-dependent manner. The virus-induced reactive oxygen species (ROS) production, apoptosis, and autophagy. Additionally, NDV treatment upregulated cytochrome-C expression while downregulating survivin levels. These results position the HB1 strain of NDV as a promising candidate for cervical cancer therapy [83]. Another study on the oncolytic NDV vaccine strain LaSota in TC-1 cells expressing HPV-16 E6/E7 antigens revealed that NDV significantly reduced cell viability and suppressed growth by inducing apoptosis through ROS production. These findings suggest, NDV as a promising selective antitumor agent for cervical cancer therapy [84]. A similar study highlighted the therapeutic potential of NDV in enhancing the efficacy of Doxorubicin for cervical cancer in mouse models. The combined treatment significantly improved survival rates, slowed tumor progression, and increased nitric oxide and lactate dehydrogenase levels in splenocytes. Additionally, it elevated TNF-α, IL-12, and IFN-γ levels while reducing TGF-β and IL-4 secretion compared to NDV or Doxorubicin alone. These findings reveal that NDV is a potent adjunct to chemotherapy for cervical cancer [85].

4. Coxsackievirus: A recent study highlighted the oncolytic potential of coxsackievirus B3 strain 2035 A (CVB3/2035 A) in cervical squamous cell carcinoma (CSCC). The virus demonstrated potent anti-tumor activity in CSCC cell lines, xenografts, and patient-derived tissue cultures and organoids. Notably, CVB3/2035 A exhibited synergistic effects when combined with paclitaxel, enhancing its therapeutic impact. These findings suggest that CVB3/2035 A could be a promising alternative or complement to existing CSCC chemotherapy regimens [86].

5. Respiratory syncytial virus: A recent study explored the antitumor activity and underlying molecular mechanisms of the oncolytic Respiratory syncytial virus- A2 (RSV-A2) in TC-1 cancer cells, a model for HPV-related cervical cancers. The results demonstrated that RSV-A2 exhibited potent cytotoxic effects on HPV-associated cervical cancer cells. It induced apoptosis and autophagy, activated caspase-3, promoted ROS generation, and inhibited the cell cycle in the TC-1 cell line. These findings highlight RSV-A2 as a promising candidate for the treatment of cervical cancer [87].

Role of OVT in the Management of Endometrial Cancer

The potential of OVT in endometrial cancer remains largely underexplored, with only a limited number of studies investigating its therapeutic applications. Despite this, OVT is rapidly emerging as a promising and innovative approach for managing endometrial cancer, offering new avenues for treatment and highlighting the need for further research in this area [88]. Few OVs have been explored to treat endometrial cancer. One study investigated the oncolytic potential of coxsackievirus B3 strain 2035 A (CV-B3/2035 A) as a novel therapeutic option. The findings demonstrated that CV-B3/2035 A exhibited strong oncolytic activity in human endometrial cancer cell lines both in vitro and in vivo, as well as in patient-derived endometrial cancer samples ex vivo. These results suggest that CV-B3/2035 A holds promise as an alternative virotherapy agent for endometrial cancer treatment [89]. Another study compared the efficacy of the Edmonston strain of measles virus and VSV against endometrial cancer and found VSV to be more effective. Intratumoral VSV led to faster tumor regression than measles virus, while intravenous VSV achieved complete tumor control in all treated mice [90].

[Table 1] depicts the role of OVT in gynecological cancers.

Table 1 Role of Oncolytic Viruses in the Management of Gynecological Cancers.

Author & Year of Study	Country of Study	OV and its type	Nucleic acid type	Study Model	Delivery Route	Main Results	Reference
OVARIAN CANCER
Kuhn, et al., 2016	United States of America & United Kingdom	Adenovirus (OvAd1 and OvAd2)	dsDNA	Ovarian cancer cell line SKOV3	Intratumoral (Virus incubated with cell lines)	Developed OvAd1 and OvAd2 OVs. Effective against platinum-resistant ovarian cancer cell lines. Neither virus caused peritoneal adhesions as observed with Ad-5.	[55]
Thomas, et al., 2016	United States of America	Herpes simplex virus armed" with murine IL-12	dsDNA	Murine and Human ovarian cancer cell lines	Intraperitoneal	Enhanced tumor antigen-specific CD8+T-cell responses in the omentum and peritoneal cavity Better control of ovarian cancer metastases Improved overall survival	[65]
Alfano, et al., 2017	Argentina	Adenovirus (AR2011)	dsDNA	Human ovarian cancer cell lines	Intratumoral (Virus incubated with cell lines)	Demonstrated potent lytic effects in vitro on human ovarian cancer cell lines and ascitic fluid-derived malignant cells.	[60]
Uusi-Kerttula, et al., 2018	United Kingdom	Adenovirus (Ad5NULL-A20)	dsDNA	Mice model and SKOV3 xenograft model of human epithelial ovarian cancer	Intravenous	OVs reduced ascites formation Extended overall survival. Enhanced T cell infiltration, activation, and effector differentiation, reprogrammed macrophages, and improved CD8+/CD4+T cell and M1/M2 macrophage ratios.	[56]
McGray, et al., 2019	Canada	Maraba virus (antigen-armed)	Negative-sense ssRNA	Mice model	Intraperitoneal/Intravenous	Elicited strong tumor-specific CD8+T cell responses Improving tumor control	[73]
Santos, et al., 2020	Finland	Adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2)	dsDNA	Cultures derived from patients with advanced ovarian cancer	Intratumoral	Reprogrammed the TME to enhance TIL reactivity. Improved clinical effectiveness of Adoptive cell therapy in patients with advanced cancer.	[59]
Hamma, et al., 2020	United States of America	Parapoxvirus ovis (CF17)	dsDNA	Human and mouse cancer cell lines	Human cell lines and Intraperitoneal injection in mice.	Reduced tumor progression in an advanced-stage cancer model. Works as NK cell-stimulating immunotherapy.	[66]
Shi, et al., 2021	China	Adenovirus	dsDNA	Mice	Intraperitoneal	Reduced ascites development in advanced ovarian cancer Prolonged overall survival. Ascitic immune microenvironment revealed promoted T cell infiltration, activation, and differentiation into effector phenotype, reprogrammed macrophages, and improved CD8+/CD4+T cell and M1/M2 macrophage ratios.	[57]
Moreno, et al., 2021	Spain	Adenovirus (Enadenotucirev plus paclitaxel)	dsDNA	Humans	Intraperitoneal	Improved progression-free survival Enhanced immune-cell infiltration within tumors Better tolerability	[61]
Gebremeske, et al., 2021	Canada	Vesicular stomatitis virus	Negative-sense ssRNA	Mice	Intravenous	Reduced tumor burden Enhanced survival and decreased metastases	[64]
Manyam, et al., 2021	United States of America	Modified vaccinia virus (Olvi-Vec)	dsDNA	Humans	Intraperitoneal	Favorable safety profile Robust immune activation Improved survival outcomes in platinum-resistant or refractory ovarian cancer	[69]
van Vloten, et al., 2022	Canada	Parapoxvirus ovis	dsDNA	Orthotopic mouse model of end-stage epithelial ovarian carcinoma	Intraperitoneal	Reduced tumor progression Anti-tumor effects highly dependent on NK cells	[67]
Opp, et al., 2022	United States of America	Sindbis virus	Positive-sense ssRNA	Mouse Ovarian Surface Epithelial Cell Line model	Intraperitoneal	Enhanced anti-tumor immune response Prevented tumor recurrence in mice rechallenged with tumor cells after 5 months	[72]
Fakih, et al., 2023	United States of America	Adenovirus (Enadenotucirev plus nivolumab)	dsDNA	Humans	Intravenous	Improved overall survival Induced immune cell infiltration and activation	[62]
Minott, et al., 2023	Canada	Parapoxvirus ovis	dsDNA	Murine model of late-stage ovarian cancer	Intraperitoneal	Enhanced immune cell infiltration into ascites TME Reduced tumor burden Improved overall survival	[68]
Holloway, et al., 2023	United States of America	Modified vaccinia virus (Olvi-Vec)	dsDNA	Humans	Intraperitoneal	Better response rate and progression-free survival in platinum-resistant or refractory ovarian cancer cases. Good safety profile	[70]
Basnet, et al., 2024	Finland	Adenovirus (Ad5/3-E2F-d24-aMUC1aCD3-IL-2 armed with human aMUC1aCD3 T cell engager and IL-2)	dsDNA	Patient-derived ovarian cancer xenograft models	Intravenous	Enhanced T cell cytotoxicity, increasing granzyme B, perforin, and IFN-γ levels. Immune profiling revealed activated gamma delta T cells and NK and NK-like T cells. Reduced exhausted CD8+T cells in ovarian ascites.	[58]
Geoffroy, et al., 2024	Canada	Vesicular stomatitis virus	Negative-sense ssRNA	Patient-derived ovarian cancer cell lines	Intratumoral (Virus incubated with cell lines)	Combining VSV with JAK inhibitors, significantly enhanced therapeutic efficacy in advanced ovarian cancer.	[63]
CERVICAL CANCER
Heideman, et al., 2005	Amsterdam	Adenovirus (CRAd AdCB016)	dsDNA	Human cervical carcinoma cell lines	Intratumoral (Virus incubated with cell lines)	Remarkable specificity in targeting HPV-positive cervical cancer and dysplastic cell lines.	[75]
Wang, et al., 2010	China	Adenovirus (M6)	dsDNA	HPV16-positive cervical cancer cell lines	Intravenous	Induces apoptosis Reduced invasiveness Enhanced overall survival in combination with radiotherapy.	[77]
Wang, et al., 2011	China	Adenovirus (M5)	dsDNA	Human cervical carcinoma cell lines	Intratumoral (Virus incubated with cell lines)	Potent antitumoral efficacy Increased killing efficacy in combination with radiotherapy.	[76]
Çuburu, et al., 2018	United States of America & Netherlands	Adenovirus types 26 and 35	dsDNA	Mice	Intramuscular and/or Intravaginal	Enhanced HPV-specific CD8+T cell responses Effective for HPV infections and cervical intraepithelial neoplasia.	[79]
Mozaffari Nejad, et al., 2020	Iran	Newcastle disease virus (Hitchner B1 strain)	Negative-sense ssRNA	Murine TC-1 cell line	Intratumoral (Virus incubated with cell lines)	Reduced T-cell viability Induced ROS, apoptosis and autophagy	[83]
Keshavarz, et al., 2020	Iran	Newcastle disease virus (vaccine strain LaSota)	Negative-sense ssRNA	Murine TC-1 cells	Intratumoral (Virus incubated with cell lines)	Reduced cell viability Suppressed tumor growth by inducing apoptosis through ROS production.	[84]
Kagabu, et al., 2021	Japan	Herpes simplex virus (T-01)	dsDNA	Human cervical cancer cell lines	Intratumoral	Potent cytotoxicity Suppressed tumor growth	[81]
Kagabu, et al., 2023	Japan	Herpes simplex virus (T-01)	dsDNA	Murine model	Intratumoral	Potent cytotoxic effect on stimulated T cells	[80]
Samadi, et al., 2023	Iran	Respiratory syncytial virus (RSV-A2)	Negative-sense ssRNA	TC-1 cancer cell lines	Intratumoral (Virus incubated with cell lines)	Potent cytotoxic effects on HPV-associated cervical cancer cells Induced apoptosis and autophagy, activated caspase-3, promoted ROS generation and inhibited the cell cycle	[87]
Hu, et al., 2024	China	Herpes simplex virus (SONC103, armed with a CRISPR/Cas9 gene editing system)	dsDNA	Murine xenograft cervical cancer model	Intratumoral	Effectively knocked down HPV16 oncogenes Reduced cell proliferation Induced apoptosis and inhibited tumor growth	[82]
Rasekhi Kazerun, et al., 2024	Iran	Newcastle disease virus	Negative-sense ssRNA	Mice	Intratumoral	Enhances efficacy of Doxorubicin Combined treatment with Doxorubicin significantly improved survival rates, slowed tumor progression	[85]
Lin, et al., 2024	China	Coxsackievirus (CVB3/2035 A)	Positive-sense ssRNA	Human Cervical squamous cell carcinoma cell lines in vitro and mouse xenograft models in vivo	Intratumoral/ Intravenous	Potent anti-tumor activity Exhibited synergistic effects when combined with paclitaxel	[86]
ENDOMETRIAL CANCER
Liu, et al., 2018	United States of America	Edmonston strain of measles virus and vesicular stomatitis virus	Negative-sense ssRNA	Mice	Intratumoral/ Intravenous	Intratumoral vesicular stomatitis virus (VSV) resulted in faster tumor regression Intravenous VSV achieved complete tumor control.	[90]
Lin, et al., 2018	China	Coxsackievirus (CV-B3/2035 A)	Positive-sense ssRNA	Human endometrial cancer cell lines	Intratumoral/ Intravenous	Potent oncolytic activity Good safety profile	[89]

Safety issues and Limitations of Oncolytic virotherapy

While OVT shows great potential, several hurdles limit its effectiveness. Effective delivery of OVs faces significant challenges. Systemic administration often leads to rapid immune clearance, while intratumoral injection is impractical for inaccessible or metastatic tumors [16] [91] [92]. The immunosuppressive TME further restricts OV spread and replication [93]. Additionally, pre-existing immunity to common viruses can neutralize OVs before they reach tumor cells, and tumors may develop resistance mechanisms, reducing therapeutic efficacy over time [16].

In addition to these, there are safety concerns associated with OVT. The most common side effects of OVT include low-grade systemic symptoms and local reactions at the injection site. Fever is the most frequently observed treatment-related adverse event, with additional symptoms such as chills, nausea, vomiting, flu-like symptoms, fatigue, and pain also reported [94]. Delivery challenges and the activation of immune checkpoints after therapy can suppress immune responses, leading to resistance. Moreover, the restricted accessibility of viral receptors in tight junctions, robust interferon-mediated antiviral defenses, and abnormalities in gene expression required for viral replication and infection reduce the ability of OVs to target and destroy tumor cells [95]. Other challenges include poor penetration into tumor masses, immune responses that neutralize the virus, off-target infections, adverse conditions within the TME, and the lack of dependable predictive or therapeutic biomarkers [96].

Monotherapies often show limited effectiveness in cancer management. OVT can be combined with other treatment modalities such as chemotherapy, immunotherapy, targeted therapies, ICIs, and adoptive cell therapies to enhance therapeutic outcomes. These combinations aim to improve response rates and overall efficacy [9] [16]. Additionally, ongoing research is exploring the potential of OVT and viral oncogenes in targeting CSCs, aiming to improve cancer management strategies [97].

Conclusion

Oncolytic virotherapy represents a groundbreaking strategy for treating gynecological cancers, with various virus platforms such as adenoviruses, herpes simplex viruses, vaccinia viruses, and reoviruses showing promising therapeutic potential. These viruses not only selectively lyse tumor cells but also reprogram the TME to enhance anti-tumor immunity. Significant progress has been made in ovarian and cervical cancers, particularly with combination therapies involving ICIs and chemotherapeutic agents, resulting in improved survival and durable responses. However, the application of OVT in endometrial cancer remains underexplored, potentially due to the relatively lower mutation burden of endometrial tumors and the challenges of optimizing virus delivery and efficacy in this context. Future efforts should focus on tailoring virus platforms to address tumor-specific challenges, improving delivery mechanisms, and combining virotherapy with emerging immunomodulatory agents. Comprehensive preclinical and clinical investigations are essential to unlock the full potential of OVT across all gynecological cancers, paving the way for innovative and personalized treatment options for patients with advanced or resistant diseases.

Study Limitations

The review is based on existing literature, which may be influenced by publication bias or the lack of unpublished studies. Future systematic reviews and meta-analyses are essential for conducting quantitative assessments and addressing potential gaps in the current research to enhance the accuracy and comprehensiveness of findings.

Declaration of use of AI

During the writing process of this paper, the author(s) used ChatGPT in order to improve the English language and clarity of the manuscript. The assistance provided was limited to enhancing the quality of writing. The author(s) reviewed and edited the text and take(s) full responsibility for the content of the paper.

Authors’ contributions

NK: Conceptualization, Literature search, Data collection, Formal analysis, Data interpretation, writing original drafts, writing review and editing, final review, and approval of the manuscript.

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