Immune landscape and response to oncolytic virus-based immunotherapy

Abstract

Oncolytic virus (OV)-based immunotherapy has emerged as a promising strategy for cancer treatment, offering a unique potential to selectively target malignant cells while sparing normal tissues. However, the immunosuppressive nature of tumor microenvironment (TME) poses a substantial hurdle to the development of OVs as effective immunotherapeutic agents, as it restricts the activation and recruitment of immune cells. This review elucidates the potential of OV-based immunotherapy in modulating the immune landscape within the TME to overcome immune resistance and enhance antitumor immune responses. We examine the role of OVs in targeting specific immune cell populations, including dendritic cells, T cells, natural killer cells, and macrophages, and their ability to alter the TME by inhibiting angiogenesis and reducing tumor fibrosis. Additionally, we explore strategies to optimize OV-based drug delivery and improve the efficiency of OV-mediated immunotherapy. In conclusion, this review offers a concise and comprehensive synopsis of the current status and future prospects of OV-based immunotherapy, underscoring its remarkable potential as an effective immunotherapeutic agent for cancer treatment.

Keywords

oncolytic virus / immunotherapy / immunotherapeutic agents / immune landscape

1 Introduction

Oncolytic virus (OV)-based immunotherapy represents a promising treatment strategy that involves the use of naturally occurring or genetically engineered viruses to selectively target malignant tissue while minimizing harm to normal cells. Over the past decade, oncolytic virotherapy has made significant progress and emerged as a promising anticancer treatment modality. In 2015, the US Food and Drug Administration (FDA) approved T-VEC as the first oncolytic virus-based drug for the treatment of advanced melanoma patients. T-VEC is an attenuated form of herpes simplex virus type 1 (HSV-1) that is genetically modified to encode granulocyte-macrophage colony-stimulating factor (GM-CSF). This landmark approval paved the way for the development of other OVs and the exploration of their potential use in various cancer types [1]. Owing to its remarkable capacity to substantially prolong the survival of patients in clinical trials in glioblastoma (GBM), G47∆ [2] became the second oncolytic herpes simplex virus (HSV)-based product to be granted approval by the Japanese Ministry of Health, Labour and Welfare in 2021. Unlike traditional gene therapy, OVs can serve not only as a transgenic vector but also as an active drug. The success of oncolytic virotherapy has further fueled research into many promising OV agents. A wide range of OVs are currently being developed for cancer treatment in both preclinical studies and clinical trials; these OVs include Newcastle disease virus (NDV) [3–6], reovirus [7–9], adenovirus (ADV) [10–15] and vesicular stomatitis virus (VSV) [16–20], among others.

Despite the potential of viruses to induce antitumor immune responses, viral infections can have varying outcomes depending on several factors, such as the pathogenic genes encoded by the virus, viral interactions with the host immune system, and the capacities of the virus to replicate and establish latency [21]. Nonetheless, the increasing knowledge on viral replication and immune response modulation has led to a growing interest in utilizing viruses for therapeutic purposes in humans. A promising approach in this regard is the use of naturally attenuated or genetically engineered attenuated viruses to selectively target specific types of tumor cells [22–28]. These OVs are modified to replicate in tumor cells, leading to tumor cell lysis while sparing normal cells. Moreover, these viruses can also stimulate an immune response against the tumor, thereby synergistically enhancing their antitumor activity [29–33].

Although OVs show great promise in treating various types of tumors, the precise mechanisms by which they induce tumor cell death are not yet fully understood. OVs have demonstrated the ability to target and destroy tumor cells through diverse mechanisms, including direct lysis of infected cells, induction of immunogenic cell death, stimulation of antitumor immune responses, and modulation of the tumor microenvironment (TME). Additionally, OVs can target and destroy tumor blood vessels, leading to tumor cell starvation and eventual death. Furthermore, OVs can mitigate tumor interstitial fibrosis, which facilitates viral spread and immune cell infiltration in the tumor (Fig.1). However, the efficacy and safety of OVs as immunotherapeutic agents may vary depending on factors such as the cancer type, viral vector characteristics, and interactions with the TME and host immune system [34]. Therefore, it is important to carefully evaluate the efficacy and safety of OVs in preclinical and clinical research and to optimize their development as immunotherapeutic agents. Here, we provide an overview of recent progress in using OVs as antitumor immunotherapeutic agents in both preclinical and clinical research. Additionally, we analyze the critical role that OVs play in overcoming the immunosuppressive TME and discuss the ongoing efforts to advance their development as immunotherapeutic agents.

2 Immunosuppression and the TME

Carcinogenesis is a complex process that involves the accumulation of genetic and epigenetic abnormalities, leading to the production of tumor-specific antigens [35]. These antigens are presented by antigen-presenting cells (APCs) via major histocompatibility complex (MHC) molecules and recognized by T lymphocytes through their T cell receptor (TCR) [36]. Additional costimulatory signals are required for the full activation of T cells, and CD28 is a major costimulatory molecule that promotes the secretion of cytokines and activation of naive T cells. Once activated, cytotoxic lymphocytes (CTLs) are transported to the tumor site to achieve immune killing of tumor cells [37]. However, this process is hindered by the highly heterogeneous TME, which is characterized by acidic conditions [38], hypoxia [39], low immunogenicity [40], and immune cell dysfunction [41]. The TME is mainly composed of tumor cells, cancer stem cells (CSCs), endothelial cells (ECs), cancer-associated fibroblasts (CAFs), tumor-infiltrating immune cells, and a dense extracellular matrix (ECM) [42,43]. Although some types of tumor tissues are highly permeable to CTLs, the expression of immune checkpoint molecules, such as programmed cell death protein 1 (PD-1)/programmed cell death protein ligand-1 (PD-L1), inhibits normal T cell immune responses. The TME also contains suppressive immune cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs), which further inhibit the immune response [44]. The immunosuppressive TME presents a great challenge to cancer immunotherapy, highlighting the need for novel strategies to overcome the associated barriers.

As the tumor progresses, complex interplay among tumor cells, the tumor stroma, and the host immune system occurs, resulting in a highly immunosuppressive TME [45,46]. Malignant tumor cells avoid immune surveillance through various mechanisms, such as downregulating major histocompatibility complex class I (MHC-I) to escape T cell recognition and expressing immunosuppressive surface proteins, such as PD-L1, to deactivate infiltrating CTLs [47–49]. Furthermore, tumor cells secrete immunosuppressive molecules, including interleukin (IL)-10, chemokine ligand 5 (CCL5), GM-CSF, indoleamine-2,3-dioxygenase (IDO), and transforming growth factor-β (TGF-β), which recruit various immunosuppressive cells, such as MDSCs, TAMs, and Tregs [50–56]. Through the interactions of these components, an immunosuppressive network is established in the TME, aided by various immunomodulatory molecules, such as reactive oxygen species (ROS), arginase-1 (Arg-1), CCL22, IL-10, and immune checkpoint molecules [41,57–60].

To counteract the characteristics of an immunosuppressive TME, various strategies have been developed to bolster the role of T cells in cancer immunotherapy [61]. These include cancer vaccines designed to induce antigen-specific T cell-mediated killing, adoptive cell therapy based on autologous tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) T cell therapy, and antigen-specific TCR therapy, which aim to increase the absolute number of antitumor immune cells [62–67]. Immune checkpoint blockade (ICB) therapy is another strategy that has shown great promise in unleashing a potent antitumor T cell response [68,69]. However, the efficacy of ICB and CAR-T cells is limited in patients with an immunosuppressive TME phenotype [70,71]. CTL-mediated antitumor effects are impeded by the immunosuppressive TME and intratumor invasion, resulting in a TME lacking T cell infiltration [72,73]. The lack of tumor antigen presentation further limits T cell activation and recognition, resulting in an immunophenotypic “cold” TME [74–76], which is frequently observed in patients with hypoimmunogenic tumors, such as colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) [77–83]. Therefore, introducing TME-reprogramming drugs as a component of immunotherapy is a reasonable treatment strategy. OVs have emerged as a prime candidate for promoting antitumor immunotherapy, serving as a multifunctional genetic engineering platform for reshaping the immune landscape of the TME.

3 Oncolytic virotherapy mediates a systemic antitumor immune response

OV infections can disrupt the delicate balance between tumor cells and the immune system to some extent. Infection of tumor cells can induce immunogenic cell death (ICD) that is central to the orchestration of the host’s antitumor immune response [84]. ICD can release tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) including calreticulin (CRT) on the tumor cell surface, as well as other factors such as high-mobility group box 1 (HMGB1), extracellular adenosine-5′-triphosphate (ATP) and heat shock proteins (HSPs) [85]. The interaction between DAMPs and pattern recognition receptors (PRRs) located on target cells initiates a complex intracellular signaling cascade [86], which ultimately leads to the activation of genes responsible for the production of inflammatory mediators. These mediators are integral to the coordinated elimination of pathogens, compromised or infected cells within the host. It has been well documented that OVs, engineered through diverse viral vectors, possess the capability to induce ICD in tumor cells by triggering several modalities of cell death, such as apoptosis, necroptosis, pyroptosis, and autophagy [87]. This highlights the potential of OV-based approaches as contributors to the induction of ICD in the context of antitumor therapeutic strategies (Fig.2).

3.1 Activation of innate immunity by OV infection

During the initial phases of viral infection, nonspecific innate immunity is rapidly activated. As a result, infected tumor cells release cytokines, such as type I interferons (IFNs) and tumor necrosis factor α (TNF-α), and chemokines, which recruit and activate innate immune cells, such as neutrophils, dendritic cells (DCs), and natural killer (NK) cells. Once recruited, these innate immune cells become activated in response to the viral infection. For instance, DCs require to undergo a process of maturation to enhance their roles as potent APCs. Different DAMPs may play different roles: CRT acts as an “eat-me” signal to elicit phagocytic responses in cells such as DCs; HMGB1 drives proinflammatory signaling pathways; ATP operates as a “find-me” signal to amplify the recruitment of immune cells; and HSPs, such as HSP70 and HSP90, are released to facilitate antigen presentation and immune activation [88,89]. Additionally, both type I IFNs and DAMPs possess the capability to directly activate NK cells, facilitating the elimination of target cells [90,91]. At the same time, the OV can lyse tumor cells, resulting in the exposure of TAAs and viral pathogen-associated molecular patterns (PAMPs) to the host immune system. DCs in the TME undergo maturation in response to joint stimulation by DAMPs and TAAs, thereby initiating an OV-mediated antitumor immune response [92,93]. This mechanism highlights the importance of the OV-induced innate immune response in the initiation of antitumor immunity and demonstrates the potential of oncolytic virotherapy as a novel immunotherapeutic approach.

3.2 Activation of adaptive immunity by OV infection

The primary mechanism underlying the antitumor effect of OVs is the tumor-specific immune response mediated by T cells. Multiple studies have demonstrated that the success of oncolytic virotherapy depends largely on T cell-mediated tumor regression [94–98]. However, various factors can inhibit the function of tumor-infiltrating T cells in the TME, thereby hampering the effectiveness of this therapy. The ultimate goal of OV-based immunotherapy is to help T cells overcome immunosuppressive obstacles so that they can achieve full activation and exert their killing activity against tumor cells [99,100].

Following the stimulation of an innate immune response by an OV, antigen-loaded APCs migrate to the draining lymph nodes and activate T cells by presenting antigens. The activated T cells then recruit additional T cells to the site of the tumor through the production of lymphocyte-recruiting chemokines and proinflammatory factors induced by type I IFNs produced as part of the response to viral infection. Ultimately, oncolytic virotherapy helps reverse the immunosuppressive immunophenotype and upregulate MHC-I expression on the surface of tumor cells, which enables T cells to overcome immunosuppression and achieve effective tumor recognition and killing.

Despite the immunomodulatory effects of OVs, further exploration is required to determine how to optimize the immune response to tumor antigens in OV-infected tumor cells while minimizing the antiviral response to viral antigens.

4 Remodeling the immune landscape: mechanisms and implications

Infection by an OV promotes the secretion of numerous cytokines by tumor cells, and the resulting lysis of these tumor cells leads to the release of various TAAs. These events not only effectively stimulate an immune response but also alter the TME (Fig.3).

4.1 Recruiting and activating DCs with OVs

DCs are powerful professional APCs that bridge innate and adaptive immune responses. However, in a suppressive TME, DCs cannot be adequately induced to mature due to the absence of stimulatory cytokines and DAMPs [101,102]. This results in low antigen-presenting activity, which is characterized by downregulated expression of CD80, CD86, and MHC II [103–105]. To address this, several research teams have proposed developing immunotherapies targeting DCs, such as DC vaccines, that can effectively activate and enrich functional DCs to stimulate antitumor immune responses [106–110]. Among these approaches, oncolytic virotherapy has attracted much attention as a potential antitumor strategy.

Previous studies have shown that coculture of a recombinant poliovirus-rhinovirus chimera with the supernatant of tumor cells can significantly stimulate the maturation of DCs. OVs provide TAAs to DCs by lysing tumor cells and promote the maturation and tissue infiltration of DCs by promoting the production of cytokines such as IFN-α, TNF-α, and IL-1, thus enabling efficient presentation of tumor antigens to T cells. Some OVs, such as measles virus, HSV, and adenovirus, can also effectively activate DCs to upregulate the expression of costimulatory molecules and enhance the ability of DCs to present antigens [111–113]. Specific replication of OVs in tumor cells can also lead to effective and sustained expression of DC-activating factors. GM-CSF plays an important role in the activation, maturation, and recruitment of monocytes and DCs [114]. A genetically engineered OV (T-VEC) based on this design is a representative new type of virus. Preclinical data have demonstrated that an OV loaded with GM-CSF has a more significant inhibitory effect on tumor growth in a therapeutic or nontherapeutic context than a recombinant virus loaded with GM-CSF. These results indicate that GM-CSF can improve the immune function of DCs in the TME and play a good synergistic role in oncolytic virotherapy [115,116].

In addition, some research teams have used recombinant expression of IL-12 [117,118] or CD40L [119,120] to improve the maturation and activity of DCs, thus enhancing the antitumor immune efficacy medicated by the OV. Studies have shown that the T-VEC combined with a MEK inhibitor (trametinib) can enhance the tumor-specific T cell response by enhancing the ability of DCs to present tumor antigens [121]. Ongoing studies on the recruitment, maturation, and antigen presentation of DCs indicate that oncolytic virotherapy plays an important role in activating DCs through a variety of mechanisms.

4.2 Harnessing T cell responses with OVs

T cells are critical in the adaptive immune response to tumors, with their effective response to tumor cells requiring coordination through multiple steps of the cancer–immune cycle. OVs can play a pivotal role in tumor immunotherapy by enhancing T cell-mediated antitumor immunity and overcoming T cell-relevant barriers. The initial activation of immature T cells occurs in the secondary immune organs through recognition of antigenic peptides presented in an MHC-antigen complex, with a sufficient abundance of tumor antigens playing a vital role in initiating T cell activation [122]. Studies have demonstrated that OVs can act as in situ vaccines by mediating an antitumor response to TAAs released by tumor cells that were lysed by the OV. Exposure to OVs can promote cross-presentation of tumor antigens, further inducing T cell activation. Incorporating TAAs into adenoviral OVs can additionally induce tumor-specific T cell responses and inhibit tumor progression [123]. Combining the administration of an OV and a neoplastic antigen can significantly increase the tumor infiltration of tumor-specific CD8⁺ cells, achieving a more significant antitumor immune response [124].

The infiltration of activated T cells into the TME is a necessary step for T cells to exert antitumor effects. The interactions between some chemokine receptors on effector T lymphocytes and corresponding chemokines may influence the transport of effector T lymphocytes to tumor sites. Deficiencies in several chemokines, including CXCL9, CXCL10, CCL4, CCL5, CXCL16, and CX3CL1, have been reported to cause T cell exclusion [73,125]. Given the importance of the chemokines CXCL9 and CXCL10 in T cell recruitment, the low levels of CXCL9 and CXCL10 expression in some tumors may explain the decreased infiltration of effector T lymphocytes in these tumor beds [126]. OVs can facilitate T cell infiltration in tumors by inducing a type I IFN-mediated immune response, releasing T cell chemokines and cytokines in the TME, and inducing the infiltration of T cells into the TME. Treatment with an OV can promote the expression of CXCL9 and CXCL10 in the TME, enhancing the infiltration of immune cells, especially cytotoxic T lymphocytes, into tumor tissues [127,128]. Despite the potential of oncolytic virotherapy to promote T cell infiltration into the TME, the construction of a recombinant oncolytic VSV strain expressing CXCL9 did not yield significant T cell infiltration [129]. As such, the underlying mechanisms by which OVs stimulate T cell infiltration into the TME require further investigation.

Effector T cell responses are dependent on T cells being able to effectively recognize tumor antigens to lyse tumor cells. Tumor cells can escape immune surveillance by reducing the expression of MHC I, hindering T cell recognition and reducing the cytotoxic effect on tumor cells [122,130]. Studies have demonstrated that OVs, such as HSV, can promote the expression of MHC molecules on the surface of tumor cells after infection. An HSV strain with the ICP47 gene knocked out was shown to significantly upregulate the expression of MHC I molecules, promoting the recognition and killing of tumor cells by effector T cells [131]. Similarly, vaccinia virus and reovirus infections have been reported to induce the expression of MHC I and costimulatory molecules, overcoming the recognition barrier protecting tumor cells from T cells and promoting T cell recognition and killing of tumor cells [96,132].

4.3 Regulating and activating NK cells with OVs

NK cells are an integral component of the innate immune system and exhibit potent cytotoxic functions against cells undergoing physiologic stress, such as virus-infected and tumor cells. NK cells demonstrate remarkable phenotypic variability and are distributed extensively in various tissues. The cytolytic function of NK cells is regulated through the expression of various inhibitory and activating receptors that recognize changes in protein expression on target cells. Unlike T cells, NK cells do not depend on TCR recognition for their cytolytic function. Instead, the balance between costimulatory and inhibitory receptors is critical for NK cell-mediated killing of activated tumor cells [133]. However, the inhibitory TME can suppress the infiltration and activity of NK cells, leading to an impairment in their cytolytic function [134].

OVs have been shown to activate NK cells through pattern recognition receptors, such as TLR2, and induce the production of type I IFNs (IFN-α and IFN-β), IL-12, and IL-28, which can enhance NK cell activity [135,136]. The cytolytic function of NK cells against tumors can also be improved through antibody-dependent cellular cytotoxicity (ADCC) using fusion proteins or antibodies of different immunoglobulin subtypes [137,138]. Additionally, molecular retargeting modification has been employed to redirect antibodies against viral DE1 to tumor cells, thereby enhancing the effect of NK cell-mediated ADCC [139].

4.4 Targeting TAMs with OVs

Tumor immune surveillance relies on the functional state of TAMs. TAMs are activated by different cytokines and can be polarized into two states, namely, proinflammatory M1-like TAMs and immunosuppressive M2-like TAMs [140–142]. Specifically, IFN-γ and lipopolysaccharide stimulation induces TAMs to differentiate into M1-like TAMs, which exert antitumor activity by expressing various chemokines to attract NK cells, DCs, and T cells to infiltrate the TME [143]. M1-like TAMs also secrete cytokines such as IFN-α and IL-12 to activate these immune cells [144]. In contrast, TAMs stimulated by IL-4 differentiate into M2-like TAMs, which promote tumor growth by secreting TGF-β, vascular endothelial growth factor (VEGF), and T cell-suppressive cytokines and facilitating tumor cell evasion from immune surveillance [145].

Oncolytic virotherapy has been shown to be effective in modulating the macrophage phenotype and enhancing antigen phagocytosis. Specifically, coculturing OV-infected tumor cells with macrophages activated by conditioned medium significantly improves macrophage phagocytic activity against tumor cells [146]. Additionally, an immune checkpoint molecule expressed by macrophages, SIRPα, inhibits macrophage phagocytic function. However, blocking CD47-SIRPα inhibitory signals using OV-expressed blockers has been demonstrated to significantly enhance macrophage phagocytosis of tumor antigens [138,147].

4.5 Overcoming immunomodulatory MDSCs with OVs

MDSCs, which are a heterogeneous population of immature bone marrow cells, exert immunosuppressive effects and proliferate during tumor progression [148]. These cells facilitate immune evasion and promote tumor invasion via various nonimmune mechanisms [149–151]. Studies have identified that MDSCs secrete inhibitory molecules, such as TGF-β, IDO, and COX2, which inhibit T cell-mediated antitumor immune responses. Furthermore, MDSCs promote tumor blood vessel formation and tumor cell growth by secreting and expressing various growth factors [152]. The inhibitory effect of MDSCs poses a significant challenge to tumor immunotherapy. Specifically, prostaglandin E2 (PGE₂) induces the proliferation and differentiation of MDSCs by binding with its receptor, thereby inhibiting T cell activity [153]. Studies have demonstrated that recruiting PMN-MDSCs to infiltrate the TME can improve the therapeutic effect of oncolytic virotherapy by limiting the antitumor immune response induced by the OV and conditionally eliminating MDSCs [154]. During oncolytic herpes simplex virus type I (oHSV-1) therapy, activation of the NOTCH signaling pathway in macrophages promotes MDSC invasion in the tumor. However, blocking NOTCH signaling can release this inhibition, activate the antitumor immune memory response, and improve antitumor efficacy [155]. Elevated levels of PGE₂ coupled with suppressive chemokine profiles and high levels of granulocytic myeloid-derived suppressor cells (G-MDSCs) were shown to result in a loss of immunotherapeutic potential. Additionally, the level of infiltrating MDSCs was negatively correlated with the efficacy of oncolytic virotherapy in an evaluation of treatment with an oncolytic vaccinia virus strain. Notably, the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD) by the oncolytic vaccinia virus strain could antagonize PGE₂ activity and significantly reduce the infiltration of G-MDSCs in the TME, thereby enhancing the antitumor efficacy of the OV [156].

4.6 Targeting immunosuppressive Tregs with OVs

Tregs are a subset of inhibitory CD4⁺ T cells that play a critical role in maintaining immune homeostasis [157,158]. Tregs regulate immune responses and prevent autoimmunity, allergies, and autoinflammatory diseases. In the TME, Tregs are usually enriched, and a large number of immunosuppressive Tregs contribute to the immunosuppressive network, leading to a poor prognosis [159]. Therefore, researchers are interested in the role of Tregs in antitumor immunotherapy and their potential clinical applications. Several strategies are focused on depleting Tregs, which appears to be effective for enhancing antitumor immunity [160–162]. Studies have shown that oncolytic virotherapy with G47Δ can significantly increase T cell infiltration in the TME and decrease the infiltration of Tregs. Treatment with CTLA-4-specific blocking antibodies can further reduce Treg infiltration and lead to more significant antitumor effects [163].

4.7 Targeting the tumor stroma with OVs

The TME is a complex network that consists of tumor cells, immune cells, stromal cells, and the extracellular stroma. Within this microenvironment, CAFs are a crucial component, influencing the formation of the ECM and the overall structure of the TME. The TME matrix plays a critical role in regulating the infiltration of immune cells and delivery efficiency of therapeutic genes. A dense TME matrix can restrict drug penetration and limit immune cell infiltration, negatively impacting antitumor therapy [164–166]. Therefore, targeting the TME matrix and improving its structure is a promising strategy for tumor treatment. Hyaluronic acid (HA), an ECM component, has been shown to promote the malignant phenotype of GBM [167]. Degradation of the ECM mediated by a protease or hyaluronidase can enhance drug permeability and alter the immunophenotype of the TME. For instance, the oncolytic adenovirus ICOVIR17 expressing hyaluronidase can mediate HA degradation in the GBM ECM and improve the TME immunophenotype [168]. Similarly, coexpression of relaxin by an OV can enhance the diffusion of an oncolytic adenovirus within the tumor, reshape the TME, and demonstrate a synergistic effect with ICB therapy [169,170]. Matrix metalloproteinases (MMPs), which are calcium dependent, zinc-containing endopeptidases, are classified into four major subgroups based on their domain structure. The expression pattern of MMPs in tumors is variable, depending on MMP function and the cancer type [171,172]. MMPs play crucial roles in cell proliferation, migration, and differentiation and are involved in angiogenesis and tumor progression [171]. Studies have shown that the expression of MMP3 is significantly upregulated in various cancer types and negatively correlated with prognosis in breast cancer, pancreatic cancer, and lung cancer [173–175]. Combining an MMP3 inhibitor with an oncolytic VSV product can significantly enhance the antitumor immune response mediated by the OV, highlighting the potential of targeting the TME matrix to achieve effective tumor therapy [176]. Furthermore, overexpression of MMP9 or MMP8 enhances oncolytic HSV interstitial transport within tumors and improves oncolytic efficacy [177,178].

4.8 Disrupting tumor angiogenesis with OVs

Tumor endothelial cells (TECs), which are derived from vascular endothelial cells (VECs), play a pivotal role in the process of tumor angiogenesis by providing nutrition to tumor cells and promoting their growth. The use of OVs to target TECs has gained considerable attention in recent years [179]. VSV has been shown to activate neutrophils to support coagulation, which damages the tumor vascular system and enhances the antitumor activity of OVs [180]. In addition, OVs can cause vascular damage and inhibit angiogenesis. Specifically, OVs induce decreased expression levels of VEGF, leading to vascular damage and inhibition of angiogenesis in mouse models of breast and kidney cancer [181]. Furthermore, an oncolytic NDV product was shown to promote acute closure of tumor blood vessels, but a combined intervention to promote vascular normalization could enhance the therapeutic effect of OVs in animal models of ovarian cancer. This normalization effect could increase the spread of OVs in the tumor and the infiltration of immune cells into the tumor bed [182]. Therefore, targeting tumor blood vessels while maintaining the infiltration process of immune cells may be an important approach to improving oncolytic virotherapy.

5 OVs as carriers of therapeutic genes to enhance tumor immunotherapy

OVs can be used as vectors to deliver therapeutic genes to tumor cells, as they selectively target and kill tumor cells without harming healthy cells. These viruses can also be modified to express therapeutic genes for increased antitumor efficacy or targeted payload delivery, making them promising candidates for cancer gene therapy.

There are several ways in which the antitumor immunotherapeutic efficacy of OVs can be enhanced. First, OVs can carry immunostimulatory cytokines and chemokines, such as IL-2 [183–185], IL-12 [186], IL-7 [187], TNF-α [184], IL-15 [188], and CXCL9 [129]. These molecules can activate and recruit T cells, APCs, and NK cells, thereby improving the antitumor activity of the OV. Second, OVs can carry costimulatory molecules, such as CD40L [120,189] and 4-1BBL [190], which promote T cell activity and enhance the immune effect mediated by the OV. Third, OVs can express immune checkpoint inhibitors, such as anti-PD-1 [146,191], anti-TIGIT [192], and an extracellular domain protein of PD-1 [96], to reduce the toxicity associated with the combination of the OV and immune checkpoint molecule-specific antibodies. Fourth, OVs can be engineered to express bispecific T cell engagers (BiTEs), fusion proteins consisting of two single-chain antibody fragments, which have demonstrated potent antitumor immune efficacy in various tumor models [193–198]. Finally, OVs can express TAAs to enhance the recognition of tumor-specific antigens by the immune system and promote a specific antitumor immune response [123,199–201].

OVs are widely used as a “platform” for tumor therapy due to their ability to selectively replicate in tumor cells, induce immunogenic cell death, promote the release of TAAs, and activate innate and adaptive antitumor immune responses. Moreover, they can be genetically engineered to express therapeutic genes to further enhance antitumor activity (Fig.4). With the development of different therapeutic combinations and innovative designs, OVs are expected to become even more promising as immunotherapeutic agents.

6 Rational combination strategies to maximize the benefits of virotherapy

OVs offer a distinct approach to combating tumors with low toxicity. Therefore, OVs appear as a reasonable candidate for potentiating the efficacy of diverse therapeutic modalities, including systemic chemotherapy, immunotherapy, targeted therapy and radiotherapy. Emerging evidences underscore the capacity of OVs to exert a notable impact on the TME, particularly in the context of promoting the upregulation of PD-L1 through type I and type II interferons induction, thereby augmenting their therapeutic responsiveness to ICB therapy [146]. The synergistic potential of this combinatorial approach has been substantiated in multiple preclinical animal models. As exemplified by a randomized phase II trial comprising 198 patients suffering from metastatic melanoma, the validated objective response rate (ORR) exhibited a substantial enhancement in the OVs/ipilimumab combination group (35.7%; 95% CI 26.3 to 46.0) in contrast to the ipilimumab monotherapy group (16.0%; 95% CI 9.4 to 24.7). Crucially, the safety profile of the combination mirrors that of individual treatments, with no discernible increase in adverse events attributable to the combined regimen [202].

Furthermore, the investigation into the synergistic potential of OVs with radiotherapy, chemotherapy, targeted therapy, and adoptive cell therapy constitutes a dynamically evolving and intensely researched frontier (Tab.1). The promising early results from these studies have kindled the fervor of researchers and developers, presenting a considerable potential for shaping the future course of OVs development.

7 Discussion

While OVs have shown promise as a therapeutic strategy for cancer treatment due to their tumor selectivity and the potential to trigger systemic antitumor immune responses, there remain several challenges that must be addressed to fully exploit their potential. In this section, we will discuss these challenges and explore strategies for overcoming them.

One critical concern regarding the use of OVs as vectors for therapeutic gene delivery lies in their in vivo infection and replication efficiency within tumor cells, which are impeded by the host’s antiviral defense mechanisms and tumor heterogeneity [203,204]. These factors limit the efficiency of OV-based drug delivery. To overcome this limitation, innovative strategies are required to enhance viral entry and replication specifically within tumor cells while evading host immune responses. Several approaches have been explored to improve tumor cell infection and replication efficiency. Genetic engineering techniques have been employed to enhance viral tropism for specific tumor types or tumor-associated receptors, enabling better targeting and entry into tumor cells [205,206]. Furthermore, modifications of viral proteins involved in viral attachment and entry, as well as evasion of host immune surveillance, have been investigated to enhance viral infectivity and replication within tumor cells [34].

Another significant challenge is the suppressive TME, characterized by immunosuppressive cells, inhibitory checkpoints, and immunosuppressive cytokines, hinders the generation of robust antitumor immune responses. To overcome immune evasion and modulate the TME, researchers have investigated combination therapies and targeted approaches. Combination therapies including OVs with other immunotherapeutic agents, such as immune checkpoint inhibitors, adoptively transferred T cells, or cancer vaccines, have also shown promising results in preclinical and clinical studies [124,146,191,207–210]. Specifically, targeting the immunosuppressive components of the TME, such as regulatory T cells or myeloid-derived suppressor cells, has shown promising results in preclinical studies [156,211]. Furthermore, the engineering of OVs to express immunomodulatory molecules or tumor-targeted cytokines represents a potential avenue for enhancing the antitumor immune response by modulating the TME.

Additionally, resistance mechanisms developed by tumor cells can impede the oncolytic effects of viruses, leading to treatment failure and disease progression. To address therapeutic resistance, researchers have explored combination strategies involving OVs and other treatment modalities. Synergistic effects have been observed when combining OV therapy with conventional chemotherapy or radiotherapy, thereby enhancing the cytotoxic effects on tumor cells. Furthermore, conducting a systematic investigation and examination of critical signaling pathways within tumor cells, coupled with the application of targeted therapies like small-molecule inhibitors or antibody-based therapeutics, provides effective approaches to bolster the infection and replication capacity of OVs within drug-resistant tumor cells [212]. Preclinical studies have demonstrated the synergistic efficacy of inhibitors targeting EGFR/KRAS/MAPK and specific metabolic enzymes in combination with OVs, suggesting their potential in overcoming resistance mechanisms associated with specific molecular alterations in tumor cells [213]. Additionally, ongoing efforts are focused on optimizing the delivery and systemic distribution of OVs, including the development of viral vectors with enhanced tumor-specific targeting, improved viral stability, and controlled release of viral particles within the TME.

In conclusion, OVs hold immense potential for cancer therapy, but further research endeavors are warranted to overcome resistance and achieving durable treatment responses. Continued investigation into improving tumor cell infection and replication efficiency, modulating the suppressive TME, and addressing therapeutic resistance will be instrumental in maximizing the clinical utility of OVs in cancer treatment.

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