Introduction

Glioblastoma (GB) is the most frequent malignant and aggressive brain tumor in adults, accounting for approximately 15% of all intracranial neoplasms and 45–50% of all primary malignant brain tumors [1]. With a peak incidence in patients aged 55–85 years. The annual age-adjusted incidence rates for GB have increased in recent years to 3–6 cases per 100,000 people [2]. Its aggressive nature is reflected in its classification as a grade 4 glioma by the World Health Organization (WHO), characterized by rapid cell division, extensive infiltration into surrounding brain tissue, and the formation of abnormal blood vessels that support the tumor’s growth [3]. The intricate challenges posed by GB extend beyond its high recurrence rate and resistance to conventional therapies. The tumor exhibits molecular and genetic heterogeneity, with distinct subtypes: gliosarcoma, giant cell GB, and epithelioid GB, each presenting unique biological behaviors and therapeutic responses [4, 5]. This diversity underscores the complexity of GB and emphasizes the need for personalized treatment approaches. Despite advancements in neuro-oncology, the GB prognosis remains poor, with a median overall survival of approximately 12 to 15 months, even with aggressive treatment strategies [6]. Current treatments like surgery, radiation, and chemotherapy have limits. This emphasizes the urgent need for innovative solutions to deal with the complexities of GB’s biology. These constraints emanate from the blood-brain barrier (BBB), imposing restrictions on the effective delivery of therapeutic agents to the tumor site. This resistance, coupled with the high rate of recurrence. Oncolytic viruses (OVs) are special viruses, either natural or genetically modified, made to specifically find and kill cancer cells [7]. GB’s unique characteristics make it an ideal candidate for oncolytic virotherapy; the viruses can navigate the intricate brain environment, overcoming barriers that hamper traditional treatments [8]. GB is known for its immunologically “cold” tumor microenvironment (TME), characterized by a lack of immune cell infiltration and an immunosuppressive environment. OVs have shown potential in transforming this “cold” environment into a more “hot” and immune-responsive state. Studies have indicated that OVs can induce immunogenic cell death (ICD), leading to the release of tumor antigens and the activation of anti-tumor immune responses [9–11]. This process involves the stimulation of various immune cells, such as dendritic cells (DCs), natural killer (NK) cells, and cytotoxic T lymphocytes, which can then target and eliminate cancer cells [12]. Additionally, OVs can modulate the TME by reducing immunosuppressive factors, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells, while enhancing the infiltration of effector T cells. Moreover, OVs stimulate the immune system, triggering a robust anti-tumor response that extends beyond the initial viral attack [13].

In unraveling the history of OVs in GB treatment, we witness not only a response to the shortcomings of conventional therapies but also a promising leap toward more effective and targeted interventions. The interaction between OVs and the neuroinflammatory cytokines in GB is a complex area of study. Neuroinflammation is a process involving the activation of inflammatory responses in the central nervous system (CNS), and cytokines play a crucial role in mediating these responses [14]. In the context of GB, neuroinflammation is often associated with the presence of tumor-associated macrophages (TAMs) and microglia, which release various cytokines [15]. When OVs infect GB cells, they can induce a local immune response. This response may involve the release of cytokines and chemokines, which can modulate the TME [16]. The specific effects on neuroinflammatory cytokines can vary depending on the OVs used, the characteristics of the tumor, and the host’s immune response [17]. Some OVs have been engineered to express therapeutic transgenes, including cytokines, to enhance their antitumor effects [17]. These transgenes can further influence the local cytokine TME and potentially stimulate an anti-tumor immune response. This review aims to focus centers on the intricate interplay between OVs and neuroinflammatory cytokines within the GB TME. We explore the therapeutic approaches of oncolytic virotherapy and OVs combined with other treatment protocols. We seek to contribute valuable insights that may pave the way for novel and personalized therapeutic strategies, offering renewed hope for patients grappling with this challenging malignancy.

GB microenvironment and its impact on tumor progression

The GB TME is a critical factor in tumor progression. It promotes invasion, immune evasion, angiogenesis, and therapeutic resistance, making GB one of the most challenging cancers to treat. The GB microenvironment refers to the complex and dynamic surroundings in which GB cells, exist and interact with neighboring cells and components [18]. GB is classified as a “cold” tumor due to several features of its microenvironment that hinder an effective immune response against the tumor. GB tumors often exhibit a low rate of lymphocyte infiltration, particularly T cells, which are crucial for anti-tumor immunity [19]. This plays a role in inhibiting primary inflammation and immune responses within the CNS, where GB develops, further limiting immune cell infiltration and function [20]. Even if immune cells manage to infiltrate the tumor, the CNS has unique immunosuppressive mechanisms that can inhibit their function, contributing to the immunosuppressive nature of the GB microenvironment [21]. Additionally, GB tumors have a relatively low mutation rate and thus a low chance of neoantigen formation, which are key targets for the immune system to recognize and attack cancer cells [22]. These features collectively create an immunosuppressive TME in GB, making it less responsive to immunotherapy. The GB TME includes various cellular and non-cellular components such as tumor cells, immune cells, blood vessels, extracellular matrix (ECM), and signaling molecules. This dynamic network of interactions contributes to the unique characteristics of GB, including its invasiveness and resistance to treatment [22]. Among the cellular components, GB cells exhibit rapid proliferation, infiltration into surrounding brain tissues, and the formation of abnormal blood vessels, which are essential for sustaining their growth. Concurrently, immune cells such as TAMs, microglia, and other immune cells play a pivotal role in the microenvironment, influencing inflammation and modulating the immune response. ECM, provides structural support and regulates cell behavior [23]. Changes in the ECM composition have a profound impact on tumor invasion and progression [24]. Abnormal angiogenesis leads to the formation of leaky and disorganized blood vessels, contributing to the tumor’s nutrient supply and growth [25]. Additionally, signaling molecules such as cytokines, chemokines, and various growth factors released by tumor cells and immune cells influence immuno-inflammatory response, and the overall dynamics of the TME [26]. OVs can remodel this hostile environment by targeting tumor cells. OVs selectively infect and replicate within tumor cells, leading to their lysis. This process releases tumor-associated antigens (TAAs) into the TME, which can stimulate an immune response by exposing these antigens to immune cells, particularly DCs. OVs can also modulate immune cell dynamics and can enhance the maturation and activation of DCs, which are crucial for effective antigen presentation. By providing novel tumor antigens and promoting DC infiltration, OVs help overcome the immune tolerance typically induced by the TME. Infection with OVs can lead to the upregulation of pro-inflammatory cytokines. This change not only enhances the infiltration of cluster of differentiation 4⁺ (CD4⁺) and CD8⁺ T cells but also restores major histocompatibility complex (MHC) class I expression on tumor cells, facilitating better recognition and destruction by T cells [12, 22]. Understanding these intricate interactions is critical for developing targeted therapeutic strategies against GB.

Neuroinflammatory cytokines: key players

Neuroinflammatory cytokines play a prominent role in the intricate dynamics of the CNS during the inflammatory response in GB. Within the GB microenvironment, immune cells, particularly TAMs and microglia, are attracted and undergo activation, releasing a diverse array of cytokines. Glioma-derived cytokines, including tumor necrosis factor-alpha (TNF-α), interleukins (ILs): IL-1α and IL-1β, IL-4, IL-6, and IL-8, play pivotal roles as inflammatory mediators. These factors trigger and sustain the inflammatory cycle in GB, while also promoting carcinogenesis. They achieve this by bypassing growth suppression mechanisms, promoting angiogenesis and metastasis, resisting apoptosis, and maintaining the stemness of cancer cells [27–29]. ILs, especially IL-6 and IL-8, play a crucial role, with IL-6 being involved in the proliferation of GB cells [30, 31]. Recent studies have identified a fourth subtype of alternative M2 macrophages, activated by IL-6 and toll-like receptors (TLRs) agonists through adenosine receptors. Activation of these receptors triggers the secretion of anti-inflammatory cytokines like IL-10 and IL-12, as well as angiogenic factors such as vascular endothelial growth factor (VEGF). These findings provide additional evidence supporting the critical role of TAMs in tumor maintenance and progression [31, 32]. In vitro and in vivo studies suggest that the interaction between protein kinase B (Akt) and IL-6 depends on the autocrine/paracrine release of IL-6. This release increases Akt activity, which in turn boosts IL-6 secretion into the TME, inhibiting caspase-3. This interplay between IL-6 and Akt promotes chemoresistance and gliomagenesis [33]. IL-6 and colony-stimulating factor-1 (CSF-1) activate mammalian target of rapamycin (mTOR), promoting cell survival and the growth of alternatively activated macrophages in the TME [34]. Additionally, several studies have shown increased nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity in various GB models [35]. IL-1β activates the NF-κB pathway by binding to the IL-1 receptor, leading to sustained stimulation of pro-inflammatory genes [36]. Transforming growth factor-beta (TGF-β) increases microRNA-182 (miR-182) levels, prolonging NF-κB activation in GB samples [37]. NF-κB activation in glioma cells upregulates the pro-angiogenic gene IL-8 [38]. Inhibition of both NF-κB and signal transducer and activator of transcription 3 (STAT3) with antagonists reduces IL-6 levels, enhancing anti-invasive and cytotoxic effects in GB [39]. IL-8 is a strong pro-angiogenic factor, especially during tumorigenesis and progression [30]. It stimulates angiogenesis by promoting endothelial cell migration and the production of matrix metalloproteinases (MMPs) [40]. Targeting IL-8 in therapies could reduce tumor angiogenesis, improve permeability, hinder GB formation, and potentially enhance drug delivery. TNF-α and interferon-gamma (IFN-γ), released by immune cells, play complex roles in inflammation and tumor progression, affecting cell invasion and interactions with surrounding tissues [41]. These cytokines also impact the BBB, altering its integrity and allowing immune cell infiltration and other factors into brain tissue [42]. This disruption adds complexity to the GB microenvironment, where cytokines influence both the immune response and potentially exert anti-tumor effects, particularly IFN-γ [43]. GB cells contribute to this dynamic by showing cytokine expression heterogeneity, highlighting the complexity of the TME. Understanding how neuroinflammatory cytokines function is crucial for developing specific treatments to improve outcomes in treating GB. Figure 1 illustrates the TME in GB, highlighting the secretions of immune cells and other cellular components.

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Figure 1. 

TME: immune and other cell secretions in GB. TAMs and microglia, along with other immune cells, secrete cytokines and chemokines such as IL-6, IL-8, IL-10, IL-12, VEGF, TNF-α, and IFN-γ, contributing to inflammation, angiogenesis, immune regulation, and tumor progression. Additionally, various other immune cells, including T cells, B cells, NK cells, and DCs, may also secrete cytokines and chemokines, further influencing immune responses and TME dynamics. Akt: protein kinase B; CCL-5: chemokine (C-C motif) ligand-5; COX-2: cyclooxygenase-2; CSF-1: colony-stimulating factor-1; CXCL-12: C-X-C motif chemokine ligand-12; DCs: dendritic cells; ECM: extracellular matrix; GB: glioblastoma; IFN-γ: interferon-gamma; IL-1α: interleukin-1α; miR-182: microRNA-182; MMPs: matrix metalloproteinases; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NK: natural killer; PDGF: platelet-derived growth factor; PGE2: prostaglandin E2; STAT3: signal transducer and activator of transcription 3; TAMs: tumor-associated macrophages; TGF-β: transforming growth factor-beta; TME: tumor microenvironment; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor. Created in BioRender. Bahari, N. (2025) https://BioRender.com/t34f628

Mechanisms of oncolytic virotherapy

Immune modulation of OVs in GB’s

The neuroinflammatory response in GB can be modulated by OVs by triggering an antitumor immune response and changing the TME. OVs are engineered to destroy specifically tumor cells, resulting in the targeted destruction of these cells [8, 50]. Thereby initiating an inflammatory immune response in the TME and the induction of antitumor immunity [7, 44, 48].

Immunoreactive cells induced by OVs

Available evidence indicates a positive correlation between tumor T cell infiltration and clinical outcomes in patients with GB, underscoring the significant therapeutic potential of T cells in GB treatment [51, 52]. Preclinical and clinical studies indicate that OVs effectively transform the “cold” immune environment of GB by triggering an inflammatory response and promoting inflammatory cell death, which leads to strong T cell activation [16, 53]. Initially, OVs replicate within tumors, causing the influx of diverse innate immune cells like NK cells and macrophages, which are linked to inflammation [16]. Following this, the pattern recognition receptors (PRRs) found on these innate immune cells can trigger a T-helper 1 (Th1) immune response by detecting either the virus or damage-associated molecular patterns (DAMPs) released when the virus lyses tumor cells. This process relies heavily on the release of IFNs, which aid in antigen presentation and the initiation of T cell-mediated adaptive antitumor immunity. As a result, augmenting T cell response against tumors through the targeting of costimulatory pathways becomes an attractive approach for GB immunotherapy [54, 55]. Incorporating T cell costimulatory molecules into OVs, such as the interaction between the costimulatory molecule OX40 and its ligand OX40L, can efficiently trigger T cell activation [56]. Delta-24-RGDOX, an oncolytic adenovirus expressing OX40L, can both recruit lymphocytes to the tumor site via ICD, like DNX-2401 (Delta-24-RGD; tasadenoturev) and activate lymphocytes that target TAAs [57, 58]. Table 1 provides information on how different OVs affect immune cells within the TME. Each OV demonstrates distinct interactions with immune cell populations, resulting in immune cell recruitment, polarization, and functional changes. These interactions play a crucial role in shaping the anti-tumor immune response and can potentially enhance the efficacy of OV therapy.

Table 1.

The effects of various OVs on immune cells in the GB tumor microenvironment

OV	Immune cells	Effect of OV	Reference
G47D-mIL-12 (HSV-1)	TAMs	Recruiting and activating dormant monocytes into M1-like macrophages. Conv Adenovirus erting existing macrophages M2-type TAMs into the macrophages M1 phenotype.	[59]
Delta-24-RGDOX (adenovirus)	Tregs	IDO expression and Treg activation. Enhanced Ovs’ anti-tumor effects through Treg targeting.	[57, 60]
oHSV (HSV-1)	Monocytes	Recruitment and polarization of non-activated monocytes into M1-like macrophages.	[61]
Poxviral infections (wild vaccinia virus)	NK cells and DCs	Recruitment and activation of pro-inflammatory M1 macrophages and other innate immune cells like NK cells and DCs.	[62]
OV-αCD47-G4 (HSV-1)	Macrophages	Transformation of M2 macrophages into the M1 phenotype.	[63]
M010 (HSV-1)	Cytokines	Chemoattractants released by OV-infected tumor cells, such as CCL-2 and CCN1, attract TAMs and other immune cells to the tumor site.	[64]
oHSV (HSV-1)	MDSC	Increasing MDSC infiltration. Reprogramming MDSCs from a pro-tumor to an anti-tumor phenotype. The recruitment of MDSCs may depend on virus type, tumor type, and timing. High levels of MDSC infiltration are associated with resistance to OV-mediated anti-tumor effects.	[65]
NDV	CD4+ T cells↑ CD8+ T cells↑, MDSCs↓	Decreasing MDSC infiltration. Reprogramming MDSCs from a pro-tumor to an anti-tumor phenotype. The recruitment of MDSCs may depend on virus type, tumor type, and timing. High levels of MDSC infiltration are associated with resistance to OV-mediated anti-tumor effects.	[66]
Adenovirus (Delta-24-RGDOX)	IFN-γ	Induction of a M1-like phenotype in TAMs, particularly around the injection site of the OV. TAMs in this M1-like state can produce IFNs and eliminate viruses through a type I IFN-dependent mechanism. Production of IFN-γ by NK cells in response to the presence of OV.	[67]
oHSV (HSV-1)	TNF-α	Secretion of TNF-α by TAMs, has been shown to be a crucial factor in inhibiting viral replication by inducing apoptosis in OV-infected glioma cells.	[63]

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CCL-2: chemokine (C-C motif) ligand-2; CCN1: cellular communication network factor 1; DCs: dendritic cells; GB: glioblastoma; HSV-1: herpes simplex virus type 1; IDO: indoleamine 2,3-dioxygenase; IFN-γ: interferon-gamma; MDSC: myeloid-derived suppressor cell; mIL-12: murine interleukin-12; NDV: Newcastle disease virus; NK: natural killer; oHSV: oncolytic herpes simplex virus; OVs: oncolytic viruses; TAMs: tumor-associated macrophages; TNF-α: tumor necrosis factor-alpha; Tregs: regulatory T cells. ↑: increase ; ↓: decrease

Inhibition of Tregs by OVs

Aside from generating strong antitumor T cell immunity, OVs also alter immunosuppressed T cell subsets. For instance, injecting DNX-2401 directly into tumors increases the presence of CD4⁺ and CD8⁺ T cells within the tumor while reducing the number of Tregs [68, 69]. Additional studies indicate that DNX2401 changes Tregs from being immunosuppressive to immunostimulatory by lowering the expression of the gene that encodes indoleamine 2,3-dioxygenase [70–72]. Therefore, blocking the activity of Tregs is a critical strategy to enhance antitumor T cell immunity [73].

Immunostimulatory cytokines produced by OVs

OVs have been shown to stimulate the immune response in GB. They can induce the production of immunostimulatory cytokines and chemokines, which in turn promote an anti-tumor immune response [74, 75]. OVs can target GB stromal cells and act on the ECM, further influencing the TME [76]. The use of OVs to stimulate the immune response in GB is an active area of research with potential implications for the development of immunotherapeutic strategies [50]. The production of immunostimulatory cytokines by OVs in the context of GB is a promising avenue for enhancing the anti-tumor immune response and warrants further investigation [77]. Cytokines represent a prevalent category of immune stimulatory factors capable of eliciting potent antitumor immunity through the recruitment and activation of T cells [78, 79]. The engineering of OVs to express cytokines such as IL-2, IL-12, and TNF has shown therapeutic efficacy in mouse tumor models [80]. Moreover, in a notable achievement, the Food and Drug Administration (FDA) approved the first oncolytic virotherapy for melanoma in 2015 [81, 82]. This modified OV includes the incorporation of the GM-CSF gene into a modified, non-pathogenic HSV type 1 (HSV-1) genome. The goal is to enhance the recruitment and activation of DCs, which are the most effective APCs for triggering T cell responses [76]. The oHSV carrying murine IL-12 (mIL-12) has exhibited a survival advantage in a mouse GB model [49, 83]. The findings strongly suggest that this survival benefit can be attributed to the heightened infiltration of cytotoxic T cells [84]. In a recent animal experiment, researchers used a combination treatment strategy that involved OVs expressing an IL-15 agonist in conjunction with epidermal growth factor receptor-chimeric antigen receptor (EGFR-CAR) NK cell therapy. This combined approach effectively suppressed tumor growth and significantly enhanced survival rates compared to using either treatment alone [85].

Shifting M2-TAM into antitumor M1-TAM by OVs

While the immune activation driven by OVs largely depends on T cells, the proper presentation of tumor antigens is also a critical factor [77, 86]. This is especially important in the GB microenvironment, where TAMs can impede lymphocyte immune surveillance. The roles of M1-TAM and M2-TAM represent two opposite ends of the spectrum in terms of the immune response [87]. M1 polarization, typically seen in the early stages of an inflammatory response, enhances T cell infiltration and initiates a subsequent adaptive antitumor response [88]. Conversely, M2-TAM in GB suppresses antigen presentation and adaptive immunity, correlating with tumor progression [89, 90]. Therefore, converting tumor-promoting M2-TAMs into tumor-killing M1-type TAMs is being explored as a potential anti-GB strategy. Studies suggest that inhibiting the expression of CD47 on tumor cell surfaces or the C-C chemokine receptor type 5 (CCR5) receptor on microglia in GB can increase the ratio of M1/M2-TAMs and improve tumor phagocytosis [91, 92]. Furthermore, IL-12, recognized for its strong ability to induce IFN-γ and drive M1-TAM polarization, demonstrates remarkable synergy in triple combination therapies when incorporated into HSV (HSV-IL12). This synergy is particularly notable when combined with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) and anti-programmed cell death-ligand 1 (PD-L1) antibodies [49, 80]. Overall, these findings indicate that polarizing TAMs towards a pro-inflammatory phenotype can establish a TME that hampers tumor progression [93, 94]. Figure 2 depicts the tactics employed by OVs to confront GB tumors.

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Figure 2. 

Strategies employed by OVs in combating GB tumors. The diagram depicts various mechanisms utilized by OVs, including enhancing anti-tumor immunity, modulating neuroinflammatory cytokines to alter the TME from a cold to a hot state, inducing cell death resulting in the release of tumor-specific antigens, shifting immunosuppressive M2-TAMs to anti-tumor M1-TAMs, leveraging bystander effects, penetrating the BBB, and suppressing Tregs. BBB: blood-brain barrier; CD4: cluster of differentiation 4; GB: glioblastoma; OVs: oncolytic viruses; TAM: tumor-associated macrophage; TME: tumor microenvironment; Tregs: regulatory T cells. Created in BioRender. Bahari, N. (2025) https://BioRender.com/r38d818

Oncolytic virotherapy for GB patients at various phases of clinical trials

GB represents a disease with a pressing need for innovative therapeutic approaches. The positive results seen in preclinical studies, demonstrating improved effectiveness without added toxicity, suggest that combining new OVs with radiation and chemotherapy could be a promising new treatment approach for GB cases [95]. The existing standard of care permits the incorporation of virotherapy as a novel therapy, enabling the evaluation of cooperative effects with radiation/chemotherapy without deviating from the established treatment protocol. Where GL261 cells were injected into anesthetized C57BL/6 mice, the use of oncolytic adenovirus (DNX2401) led to an increased infiltration of CD4⁺ T cells and T-bet⁺CD8⁺ T cells [49, 52]. Likewise, injecting the Zika virus (ZIKV) directly into tumors triggers an inflammatory response that activates microglia and myeloid cells. This activation boosts antigen presentation and contributes to an antitumor effect mediated by CD8⁺ T cells [96]. Numerous OVs targeting GB have progressed through different stages of clinical trials. Notable candidates such as DNX-2401 (Delta-24-RGD; tasadenoturev), Toca 511 (vocimagene amiretrorepvec), PVS-RIPO (recombinant nonpathogenic polio-rhinovirus), and G207 have reported results from phase-I clinical trials [7, 97]. DNX2401, an oncolytic adenovirus that selectively targets tumors, has demonstrated encouraging outcomes in phase-I clinical trials. Published data indicates that the median overall survival of GB patients treated with DNX2401 reached 9.5 months. Importantly, 20% of these patients survived for more than 3 years after treatment, indicating a positive and long-lasting response in a subset of individuals. Additionally, following treatment with DNX2401, the tumor site exhibited signs of inflammation and necrosis [50]. Histopathological analysis showed the infiltration of CD8⁺ T cells and T-bet⁺ cells [98]. This finding indicates that DNX-2401 not only causes tumor regression through direct oncolysis but also triggers an antitumor immune response, which is consistent with results from preclinical studies [52, 69]. Combining DNX2401 with other treatments has advanced to phase-I/II clinical trials, including trials registered under NCT02798406, NCT02197169, and NCT01956734 [99]. Toca 511, another potential treatment, is a retrovirus that carries the cytosine deaminase gene. This virus can replicate selectively in tumor cells, producing cytosine deaminase. The cytosine deaminase enzyme encoded by Toca 511 converts the prodrug 5-fluorocytosine (5-FC) into the active chemotherapy drug 5-fluorouracil (5-FU) [100, 101]. This enzymatic process enables targeted chemotherapy within the tumor, minimizing the potential for systemic toxicity linked to 5-FU [102]. In an earlier investigation, GB patients treated with Toca 511 therapy had a median overall survival of 14.4 months. Additionally, five complete remissions were notably observed [103–105]. PVS-RIPO has demonstrated encouraging outcomes in treating recurrent GB, with a median overall survival of 24 months [106, 107]. PVS-RIPO employs a dual approach to directly eliminate cancer cells while simultaneously triggering an immune response in the host. These two modes of action are intricately linked both mechanistically and biologically, as evidenced by the immunostimulatory process of ICD. ICD is a non-canonical form of cell death induced by viruses, which promotes an immune response against the antigens present in the deceased cells. This process involves apoptosis accompanied by the release of adenosine triphosphate, the proinflammatory cytokine high-mobility group box 1, and calreticulin [108]. These released molecules immediately lead to the recruitment of DCs, antigen presentation to cytotoxic T lymphocytes, and activation of gamma-delta T cells [109]. As far as we know, 2Apro is the initial enzyme produced by PVS in tumor cells it infects [106]. Another way this virus causes cell death is through 2Apro, which is a protease that cleaves the cell’s normal protein synthesis machinery, potentially resulting in cell death [110]. Additionally, there is ongoing investigation into combining pembrolizumab, a PD-L1 inhibitor with this therapy, which has progressed to phase-II clinical trials (NCT04479241). Table 2 outlines the ongoing clinical trials using OVs for treating GB [99]. Vaccinia virus (TG6002) and adenovirus (DNX2401) show tumor-specific replication and microenvironment modulation, while reovirus and HSV variants (e.g., M032) leverage immune stimulation through GM-CSF or IL-12. PVS-RIPO demonstrates effective targeting of PVS receptor (CD155)-expressing cells with reduced neurotoxicity, and parvovirus H1 combines oncolysis with immune responses during the S-phase. However, challenges remain, including the immunosuppressive GB microenvironment, limited OV delivery across the BBB, and potential off-target effects. Further research is needed to optimize combination therapies, refine delivery methods, and identify biomarkers for patient selection, ensuring safety and efficacy in clinical applications.

Oncolytic virotherapy in GB: challenges and perspectives strategy

Recent advancements in GB treatment, such as oncolytic virotherapy and immunotherapy, offer hope for patients. These approaches target GB cells while sparing healthy tissue. However, challenges remain, despite promising results, limiting the effectiveness of oncolytic virotherapy for GB.

OVs combined with current therapies for GB treatment

Conclusions

The GB TME presents a challenging landscape for effective treatment due to its immunosuppressive nature and resistance to therapies. Neuroinflammatory cytokines play a crucial role in shaping this environment, promoting tumor progression and immune evasion. Understanding these interactions is key to developing targeted therapies. OVs offer a promising approach to modulating the GB TME. They can induce tumor cell lysis, release TAAs, and trigger an inflammatory immune response, enhancing antitumor immunity. Clinical trials with OVs, including those expressing cytokines like IL-12, show potential in treating GB. Future research should focus on optimizing OV therapy for GB. This includes addressing challenges such as restricted distribution within the tumor and clearance by host immunity. Combining OVs with other therapies, such as ICIs, DCs, NK, and CAR-T cell therapy, holds promise in enhancing therapeutic efficacy. Additionally, further understanding of the interactions between OVs and the GB microenvironment is needed to develop more effective immunotherapeutic strategies. Overall, OVs represent a promising avenue for improving outcomes in GB treatment, and continued research in this area is essential for advancing cancer therapy.