Introduction

In recent years, early diagnosis of some cancer types, along with the development of cancer-specific treatments, has led to an increase in cancer patients' survival rates [1]. However, the short half-life of several cancer-specific medications, restricted distribution to particular tumor types, and negative impacts on healthy tissues are important barriers to treatment. Actually, the primary goal of cancer treatment is to develop anticancer medications that effectively target malignant cells while preserving healthy tissue [2, 3]. A few instances of metastatic cancer have been effectively treated using traditional methods [4]. As a result, develo** a novel therapeutic approach to inhibit metastasis is crucial, especially given the issues with current cancer treatment strategies, such as drug resistance and systemic side effects [5, 6].

Beyond the capacity of some viruses to mediate oncogenesis and their use in the development of immunotherapies, such as the cytomegalovirus (CMV) gliomagenesis and its implications in the development of CMV-specific adoptive T cell immunotherapies, viruses themselves can be used as therapeutic agents to target tumor cells [7]. In this way, oncolytic viruses (OVs) are defined as naturally occurring or genetically manipulated viruses that exclusively replicate and grow in tumor cells and kill them while sparing normal cells [8, 9]. Oncolytic viral therapy is a new strategy of cancer therapy that has shown promise in preclinical and clinical trials [10, 11]. Altered mutants of human viruses, wild-type animal viruses that are cytotoxic to human cancer cells, and live virus vaccines are among the viruses used in this therapy. Adenovirus, measles virus, reovirus, herpes simplex virus, vesicular stomatitis, Newcastle disease virus, vaccinia virus, and poliovirus are some of these viruses [12, 13]. OVs have the ability to directly lyse cancer cells but this is not the sole advantage of them; it is now well acknowledged that one of the most essential aspects of virotherapy is the cytotoxic immune response they can trigger or reactivate in patients, which results in therapeutic responses [14, 15] and was shown in glioblastoma, B cell malignancy, metastatic melanoma, and liver cancer [16,17,18,19,20]. Indeed, multiple investigators have reported on the possible use of OVs for cancer treatment, with a demonstration of long-term prognosis [21]. A variety of factors, including viral elimination by the immune system and viral uptake by tissues and organs, can influence viral effectiveness in reaching cancerous tissues [22, 23, 24]. To boost treatment efficacy, effective carrier vehicles are essential for delivering OVs to tumor sites. Adult stem or progenitor cells have been extracted from a variety of tissues, including the brain, heart, and kidney, and have shown promise in treating a variety of diseases [25,26,27]. In both in vitro and many murine cancer models, unmodified MSC has been demonstrated to have anti-tumor activities. This is due to antitumor substances generated by MSCs, which limit the growth of cancer cells including glioma, melanoma, lung cancer, hepatoma, and breast cancer [28,29,30,31,32,33]. Furthermore, MSCs have been utilized as carriers because of their known tumor-specific homing ability, which allows for the virus's safe transportation and releases on the tumor site [34,268, 269]. In spite of the route of injection of MSCs [270].

Furthermore, biological targeting techniques have been developed to satisfy the demand for greater target stringency following systemic administration of MSCs, particularly when the disease to be treated is extensive, as in metastases [271, 272]. It includes evidence-based techniques aiming at enhancing MSC homing, binding selectivity to a target tissue, and persistence within the target environment [262]. Indeed, to regulate MSC homing potential, various approaches have been established, including altering the MSC culture conditions to promote the production of homing-related compounds, redesigning the cell membrane to increase homing, and adjusting the target tissue to better attract MSCs [273].

OV penetration

Epithelial junctions function as an obstacle to the intracellular infiltration of OVs, particularly adenoviruses, in carcinomas [274]. Indeed, phenotype changes during metastasis, including EMT and later mesenchymal-to-epithelial transitions (MET), which tighten epithelial connections and make therapy challenging [275, 276]. Yumul et al. created epithelial junction openers (JO) by modifying Ad5Δ24. They found that oncolytic Ads that express JO had a substantially higher anti-tumor activity than unmodified viruses [274]. Moreover, the extracellular matrix (ECM) and cellular connections are significant barriers that are related to the spread and penetration of OVs. In fact, OVs must cross the complex ECM to reach tumor cells and lysis them [277]. Pre-treatment of cancer with collagenase [278] or co-administration of hyaluronidase with oncolytic adenoviruses [279] resulted in increased viral dissemination. Additionally, altering OVs to express matrix metalloproteinases-1 and -8 causes cancer-associated sulfated glycosaminoglycans to be degraded, resulting in improved viral dispersion and treatment efficiency [280]. Tumor cell apoptosis also promotes viral dissemination. For instance, Nagano et al. found that cytotoxic substances induced apoptosis and activated caspase-8, resulting in greater intratumoral uptake and anti-cancer effect of oncolytic HSV. They hypothesized that reducing or eliminating apoptotic tumor cells resulted in channel-like structures and empty areas, enabling oncolytic HSV to disseminate more easily [281].

Hypoxic effect

Hypoxia is a characteristic of solid tumors that emerges throughout the formation and development of the tumor and has been demonstrated to have paradoxical impacts on OVs [282]. Hypoxic circumstances have been observed to decrease viral proliferation and lytic capacity without changing the expression of surface receptors [283, 284]. Because hypoxia may cause cell cycle arrest, this feature might influence the capability of oADs and other viruses that rely on cell cycle advancement to reproduce [284]. Clarke et al. created an oncolytic adenovirus in which the expression of the E1A gene is regulated by the hypoxia-response factor-containing promoter to counteract hypoxic suppression of viral reproduction and to get the benefits of hypoxic conditions for homing [285]. However, in 2009, two groups revealed that a hypoxic condition increases oncolytic HSV viral proliferation [286, 287]. This might be due to HSV's intrinsic affinity to low-oxygen cells or DNA damage caused by oxygen-derived free radicals, which promotes HSV reproduction [286].

Treatment durability

Tumors frequently recur after great initial treatment results. Stem cell treatment using a single substance, like other chemotherapies, isn't always successful in removing tumors [288, 289]. As a result, a reasonable medication combination should be determined [290]. Many different combination therapies have been tried to see whether they can help with treatment persistence. For instance, irradiating cancer cells leads them to release molecules that promote MSC penetration across integral basement membranes, resulting in an increase in the amount of MSCs in cancers [291].

Modification

In addition to their inherent potential to lyse cancer cells, OVs can be modified to improve their lytic activity. For example, adenoviruses expressing the herpes simplex virus-1 thymidine kinase (HSV-1 TK) under the osteocalcin promoter have been designed to target bone cancers. HSV-1 TK could convert thymidine analogs, such as ganciclovir into monophosphates, which stop DNA synthesis and trigger cell death By incorporating into the DNA of reproducing cells [292, 293, 294]. OVs have been modified to improve immune responses even further. Most transgenes are designed to induce an adaptive immune response against cancer antigens or to contribute to the treatment of immune cell-depleted malignancies. Including, cytokines, chemokines, inhibitory receptors, co-stimulatory receptors, bispecific cell engagers, immunological ligands, and combinations of any of these [133, 295, 296]. For instance, researchers have engineered oncolytic viruses which can express IL-2, IL-12, IL-15, IL-6, IL-21, IL-18, IL-24, and granulocyte–macrophage colony-stimulating factor (GM-CSF) and activate various aspects of the immune system [295, 296]. Moreover, the immunosuppressive TME might be altered by inserting an immune stimulatory chemical into OV genomes. The most often utilized example is GM-CSF, which has been inserted into OV genomes as an immune stimulatory molecule to promote the maturation and recruitment of APCs, particularly DCs, as well as the recruitment of tumor antigen-specific T cells and NK cells [109]. On the other hand, one aspect of transgenic-armed OVs is that immune activation can be delayed depending on the viral promoter that regulates the transgene or by controlling protein translation. To avoid an overly-rapid immune response, the expression of transgenes should be postponed until the viral oncolysis is at its maximum [297]. Additionally, the kind of transgenic and the number of transgenes that may be included in a single viral construct are both influenced by the type of virus. Unlike DNA viruses, which can handle more transgenes without harming replication, RNA viruses generally have a shorter genome and can only encode a restricted number of them [133]. Furthermore, a modified oncolytic adenovirus expressing the TRAIL gene was recently utilized to treat a mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignant and lethal malignancy with a poor prognosis and few treatment options. The study revealed that in a PDAC animal model, AD-MSCs carrying TRAIL specifically homed to the cancer site and significantly slowed tumor growth, with no toxicity or adverse effects [178].

MSCs can be also genetically manipulated or preconditioned to increase their intrinsic features, such as improved migration, adhesion, and survival, as well as reduced premature aging. For example, to improve MSC migration, CXCR1, 4, and 7 were overexpressed which CXCR1 binds to IL-8 and CXCR4 and CXCR7 bind to SDF-1. Also for increasing MSC adhesion ability, MSCs were genetically engineered to express higher levels of integrin-linked kinase (ILK) [298].

Conclusion and prospect

MSCs improve the anticancer efficacy of virotherapy in a variety of ways. Indeed, MSCs act as a reproduction site for OVs, allowing for the generation of more virions, which is advantageous for virotherapy. In addition, MSCs' tumor tropism and immunosuppressive activity enable the virus to specifically target the cancer site, increasing viral spread, and survival. MSCs, on the other hand, generate cytokines that attract immune cells to the TME, increasing the anticancer immune response. Moreover, oncolysis triggers the production of danger signal including TAAs and DAMPs/PAMPs, which stimulate local anticancer immune responses and alter the TME from immunosuppressive to immunostimulatory [45, 51].

Integrating MSCs with more effective OVs is a reasonable move towards enhancing therapeutic outcomes. Currently, there are four ongoing clinical trials using the OV-loaded MSCs for cancer therapy, which offer up a wide range of combinations with MSCs [299].

Altogether, further development of MSCs-OVs therapies may rely on a multifaceted strategy to select design parameters to improve the safety profile and efficacy of carrier cells, improve viral replication in MSCs, and establish patient eligibility criteria. For overcoming these obstacles some efforts have performed. For example, by manipulating the MSCs, it is feasible to enhance the clinical result. Polymers or other viral capsids might potentially be used to improve infectivity and viral replication [300, 301]. Also to control the adenovirus’s replication within MSCs, an all-in-one Tet-on system has been developed, which could help future studies to reach the optimum therapeutic effect of the oncolytic virus [183].

To summarize, although existing clinical trials will help to clarify the therapeutic efficacy of MSCs as OV cell carriers, further efforts should be undertaken to translate current viral and cellular preclinical achievements to the clinic, either as monotherapy or in combination with radiation, chemotherapy, or even immunotherapies.