Inhibiting key targets in signaling pathways related to cell proliferation can enhance the replication of OVs and their oncolytic effects, thereby exerting antitumor activity. The mitogen-activated protein kinase (MAPK), Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways are jointly involved in regulating cell proliferation, differentiation, survival and apoptosis, with complex crosstalk between them. MAPK kinase (MEK) is one of the key targets in the MAPK signaling pathway (16). Lee et al (17) demonstrated that inhibiting MEK phosphorylation can activate STAT3, thereby promoting oncolytic vaccinia virus (OVV) replication in doxorubicin-resistant ovarian cancer and enhancing the anti-tumor effects. STAT3 activation also promotes the replication of oncolytic herpes simplex virus (oHSV) in glioma cells (18). MEK inhibitors also suppress the antiviral response facilitated by IFN signaling through STAT1/STAT2-dependent pathways. IFNs orchestrate innate immune responses, serving as a formidable first line of defense against pathogen invasion (19). This initiates a signaling cascade through the JAK-STAT pathway (20). STAT1 and STAT2 play pivotal roles in type I and type II IFN signaling, significantly contributing to the cellular antiviral response and adaptive immunity. The primary pathways through which IFNs exert their antiviral effects include the oligoadenylate synthetase-ribonuclease L system and the RNA-dependent protein kinase (PKR) pathway, which degrade viral RNA and inhibit viral protein synthesis, respectively. Zhou et al (21) found that trametinib boosts viral replication in BRAF V600E and BRAF wild-type (wt)/KRAS mutated tumor cells by reducing STAT1 and PKR phosphorylation. Additionally, the JAK-1/2 inhibitor ruxolitinib increases vesicular stomatitis virus (VSV) replication by inhibiting the JAK/STAT signaling pathway, enhancing its sensitivity in melanoma and lung cancer (22,23). Targeting the Cysteine-rich 61 (CCN1)-AKT pathway can enhance bevacizumab's effectiveness by reducing glioma infiltration. Elevated CCN1 expression is associated with increased AKT phosphorylation in tumor cells (24). Studies have shown that CCN1 stimulates the expression of PI3K/AKT in various types of cancer cells, including glioma, breast cancer, gastric cancer and renal cancer cells (25-27). Rapid antiangiogenesis mediated by oncolytic virus (RAMBO) is an engineered oHSV designed to express angiogenesis inhibitors and is capable of suppressing the expression of CCN1 (28). A study found that the angiostatin produced by RAMBO can inhibit bevacizumab-induced CCN1 expression, reducing bevacizumab-induced glioma infiltration by blocking the CCN1-AKT signaling pathway, thereby enhancing the efficacy of bevacizumab against malignant gliomas (28).

Tyrosine kinase inhibitor (TKI) synergistically augments the antitumor efficacy of OVs by inhibiting the phosphorylation of AKT, which are activated by OVs. G47Δ-mIL12, an advanced version based on the third-generation oHSV-1 G47Δ, enhancing tumor-specific replication and safety by deleting the α47 gene and US11 promoter to prevents class I major histocompatibility complex (MHC) downregulation and inhibiting angiogenesis (4,29,30). Research conducted by indicates that the selective TKI axitinib enhances the antitumor effect of G47Δ-mIL12 in glioblastoma (GBM) by blocking the platelet-derived growth factor receptor (PDGFR) pathway, inhibiting phosphorylated ERK1/2 and reducing G47Δ-mIL12-induced AKT phosphorylation. Furthermore, this combination also promotes apoptosis and affects stem-like cell characteristics (31). TKI can also promote OV replication by inhibiting the antiviral response mediated by IFN signaling. Research by Jha et al (32) demonstrated that multi-target TKI sunitinib weakens the antiviral response by inhibiting VSV-induced activation of the IFN pathway, thereby enhancing VSV replication.

IFN is also a key pathway in antiviral immunity, and the transcription of IFN-regulated genes induced by the JAK/STAT pathway inhibits OVs replication through multiple mechanisms (19). By inhibiting the type I IFN pathway to weaken the antiviral response of specific tumor cells, thereby enhancing the spread and oncolytic activity of OVs in tumor cells. Trastuzumab-DM1 (T-DM1), an antibody-drug conjugate, consists of the targeted therapeutic agent trastuzumab linked to the microtubule-disrupting agent and mertansine derivative DM1. This conjugate primarily exerts its microtubule-inhibiting effect in human EGFR2 (HER2)-overexpressing tumor cells through the specific targeting of trastuzumab (33). Arulanandam et al (34) found that T-DM1 targets HER2-overexpressing tumor cells to release DM1, which inhibits the type I IFN pathway and enhances the cytotoxic effect of TNF-α on neighboring cells, thereby increasing the spread and oncolytic effect of the VSVΔ51 virus in VSV-resistant cancer cells. This study did not emphasize the antitumor effect of trastuzumab itself (34). In addition, IκB kinase inhibitors BMS-345541 and TPCA-1 enhance VSV replication by inhibiting type I IFN-mediated antiviral responses, thereby improving the efficacy against glioma (35).

Targeted drugs combined with OVs enhance cytotoxic effects on tumor cells in the TME by activating immune cells, promoting cytokine release and reducing immunosuppression. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that expand in inflammation and tumors and are effective inhibitors of T cell-mediated immune responses (36). Lawson et al (37) found that sunitinib can alleviate immunosuppression induced by coxsackievirus, such as the accumulation of MDSCs, and stimulate the number of immune-stimulating cells, enhancing the anti-tumor immune response in mouse renal cell carcinoma and lung squamous cell carcinoma. Similarly, Moehler et al (38) found that sunitinib with H-1 parvovirus significantly boosts immune stimulation in melanoma. S100A8/9 are low-molecular-weight calcium-binding proteins, which can regulate the accumulation of MDSCs (39). Chai et al (40) confirmed that neural stem cell-delivered OV combined with S100A8/9 inhibitor paquinimod enhanced anti-GBM efficacy by increasing T-cell infiltration, shifting macrophages to a pro-inflammatory phenotype and reducing MDSCs. A recent study reported that KRAS inhibitors themselves promote innate and adaptive immunity, and when combined with OVV, they reduce immunosuppressive cells such as MDSCs and T-regulatory cells (Tregs) in the TME, synergistically enhancing antitumor effects (41).

TANK-binding kinase 1 (TBK1) inhibitors promote OVs replication and their sensitivity to resistant cells by enhancing immune cell responses. Intercellular adhesion molecule 1 (ICAM-1) is a cell surface receptor used by immune cells for adhesion and migration, and it is often upregulated during viral infections (42). TBK1 is a serine/threonine kinase, and its increased expression or abnormal activity can promote the survival and proliferation of cancer cells (43). Guo et al (44) reported that TBK1 inhibitors can promote VSVΔ51 replication by enhancing ICAM-1-mediated natural killer (NK) cell immunity and increase the sensitivity of VSVΔ51 to chemoresistant colorectal cancer cells.

MEK inhibitors enhance viral replication by decreasing TNF-α secretion and blocking its apoptotic effects. Due to early cell death from TNF-α-induced apoptosis, the replication and antitumor impact of oHSV-1 are limited (45). Yoo et al (46) discovered that the MEK inhibitor trametinib inhibits apoptosis in GBM cells following oHSV infection by reducing TNF-α levels, thereby promoting viral replication. Furthermore, oHSV aids trametinib in crossing the blood-brain barrier and prevents MAPK pathway reactivation, enhancing tumor sensitivity to MEK inhibition.

Proteasome inhibition promotes OVs replication by increasing the expression of heat shock proteins (HSPs). HSP90 has previously been shown to be important for the nuclear localization of HSV polymerase (47). In line with this, Yoo et al (48) found that in head and neck squamous cell carcinoma, ovarian cancer, malignant peripheral nerve sheath tumor and glioma, the proteasome inhibitor bortezomib increases the expression of HSP90 by inducing unfolded protein response accumulation, thereby promoting oHSV-1 replication and enhancing antitumor efficacy.

Using OVs to infect tumor cells allows targeted drugs to be released and connects their targets with immune cell receptors to enhance cell-killing effects. Tian et al (49) created OV-Cmab-CCL5, an oHSV encoding a bispecific fusion protein that combines cetuximab's IgG1 form with C-C motif chemokine ligand 5 (CCL5). This targets EGFR and CCL5 receptors to increase CCL5 levels in tumors and boost immune cell infiltration. It can also enhance the killing effect on GBM cells by promoting antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity through linking Fcgamma receptors on macrophages and NK cells with EGFR on tumor cells.

Poly ADP-ribose polymerase (PARP) inhibitors (PARPi) enhance antitumor effects by blocking DNA repair induced by OVs, causing persistent DNA damage and promoting cancer cell death. The dl922-947, a second-generation oncolytic adenovirus with a 24-base pair deletion in the E1A-conserved region 2, enhances viral genome production in host cells (50). Passaro et al (51) found that DNA damage induced by dl922-947 activates the PARP repair mechanism in the DNA damage response signaling pathway, while the PARPi olaparib can restore PARP activation induced by it and exacerbate DNA damage, thereby promoting apoptosis and enhancing the anti-tumor efficacy against thyroid cancer. The same antitumor mechanism was observed in the treatment of melanoma with reovirus type 3 Dearing strain (ReoT3D) combined with talazoparib (52). Recent research reports that PARP1 has been identified as a replication restriction factor for HSV-1, and olaparib promotes viral replication by inhibiting PARP1, thereby enhancing antitumor efficacy in GBM and triple-negative breast cancer (53).

Furthermore, the combination of OVs and PARPi can induce excessive reactive oxygen species (ROS) production, leading to increased DNA damage and S-phase arrest, thereby enhancing the inhibition of tumor cell proliferation. While ROS are common in cells, excessive ROS can cause cell death (54) and activate oncogenic pathways, leading to DNA damage and genetic instability (55). PARPi can have antitumor effects by increasing ROS and ROS-induced DNA damage (56,57). The measles virus (MV) is a promising alternative virus (58), which has been proven to exert oncolytic effects on ovarian cancer through ROS-induced apoptosis (59). Zhang et al (60) discovered that the recombinant Chinese Hu191 MV (rMV-Hu191) modified by a viral reverse genetic system, works with olaparib to enhance oxidative DNA damage in pancreatic ductal adenocarcinoma cells by increasing ROS levels. This combination also significantly halts the cell cycle in the S phase and inhibits cell proliferation by blocking DNA division (60).

In mammalian cells, p53 and cyclin-dependent kinases jointly manage the G1/S transition, linking apoptosis to cell cycle progression (61). Irinotecan is a topoisomerase I inhibitor that can induce the expression and phosphorylation of the tumor antigen p53, promoting the expression of apoptosis-regulating factors (62). Napabucasin (BBI608) is a stem cell inhibitor that can directly inhibit the transcription of STAT3-derived genes and can also indirectly inhibit other related genes and pathways (63). Babaei et al (64) found that combining ReoT3D, Irinotecan (CPT-11) and BBI608 significantly reduced the S phase of CT26 cells, arrested them in G0/G1 and G2/M phases, induced apoptosis by causing a sub-G1 fraction to form and downregulated KRAS and STAT3 mRNA.

Autophagy is a fundamental biological process that is crucial for preventing cellular damage, maintaining cell survival during nutrient scarcity and responding to cytotoxic stimuli. The regulation of autophagy by the PI3K/AKT/mTOR signaling pathway allows tumors to exploit this process for survival benefits through the dysregulation of the pathway (65-67). Everolimus (RAD001) is a widely used mTOR inhibitor that targets mTOR complex 1 and inhibits autophagy (68). Alonso et al (69) demonstrated that the combination of RAD001 with Delta-24-RGD, an oncolytic adenovirus with a 24-base pair deletion in the E1A gene (70), induces autophagic cell death and enhances anti-glioma efficacy, although the precise underlying mechanism remains to be elucidated. The anti-angiogenic and immunosuppressive properties of RAD001 may also contribute to these outcomes. Furthermore, they revealed that Delta-24-RGD increases glioma cell sensitivity to RAD001 by circumventing G1 phase arrest, without impacting the replication of Delta-24-RGD, indicating an additional potential anti-tumor mechanism.

The above content regarding composite molecular machineries involves various targeted drugs that exhibit significant differences in targets, mechanisms of action and tumor sensitivity. MAPK inhibitors primarily act on kinases within the MAPK pathway, such as BRAF, MEK and ERK. MEK inhibitors promote OVV replication by activating STAT3 and can also increase viral replication by reducing antiviral responses through the inhibition of STAT activation. TKIs synergistically enhance antitumor effects by reducing AKT phosphorylation activated by OVs, while OVs engineered to specifically express endostatin can increase tumor sensitivity to bevacizumab by inhibiting AKT. Pathway inhibitors can also suppress targets related to the IFN antiviral pathway, promoting OV replication. The presence of immunosuppressive cells in the TME is also a key reason for poor efficacy. Targeted drugs combined with OVs synergistically enhance antitumor effects by boosting innate and adaptive immunity and reducing immunosuppression. PARPi primarily target PARP enzymes responsible for repairing double-strand DNA damage, exerting antitumor effects by inducing sustained DNA damage through increased ROS and inhibition of OV-induced DNA repair. Furthermore, OVs can synergize with inhibitors related to apoptosis and autophagy pathways for antitumor effects (Fig. 1). The different characteristics of these inhibitors provide clearer guidance for selecting targeted drugs in combination therapy. Choosing the appropriate drugs based on tumors with different target mutations can markedly enhance the precision and antitumor efficacy of combination therapy. Due to the numerous molecular target mutations in tumors, a wide variety of targeted drugs have been developed and approved for use. However, the exploration of combination studies remains limited, with the combined mechanisms focusing only on major pathways such as MAPK, JAK/STAT and PI3K/AKT. The Wnt, Notch and Hippo signaling pathways, which also play important roles in multiple cancers (71-73), have not yet been reported, to the best of our knowledge. The potential interactions between OVs and the toxic side effects of the targeted drugs themselves could reduce the therapeutic window and introduce unpredictable pharmacokinetics/pharmacodynamics. Furthermore, this strategy also has some inherent limitations. Tumor heterogeneity may lead to certain tumors being insensitive to both treatments, and since OVs are mainly administered via local injection, their efficacy against distant metastatic lesions is limited. The use of certain potent apoptosis-inducing targeted drugs may prematurely eliminate OVs, which in turn could restrict viral replication.

Overactivation of signaling pathways is a cause of cancer pathogenesis, being involved in various tumors and playing a critical role in guiding clinical treatment choices and classification (115). Different gene mutation statuses, such as EGFR and KRAS mutations in lung adenocarcinoma, show significant differences in biological behavior and clinicopathological features, leading to completely different treatment options (116). In breast cancer, classification is based on the expression of estrogen receptor, progesterone receptor and HER2 (Luminal A, Luminal B, HER2-positive, triple-negative), which directly determines subsequent treatment strategies (117). Once the key signaling pathways driving tumor growth are identified, targeted drugs can be developed against critical nodes in these pathways. These pathways can also serve as predictive markers for evaluating treatment efficacy and prognosis. For instance, phosphatase and tensin homolog protein loss leading to overactivation of the PI3K-AKT pathway in prostate cancer generally indicates poor prognosis (118). Single-cell RNA sequencing suggests that the C2 insulin-like growth factor 2 tumor subtype is associated with poor prognosis in high-grade serous ovarian cancer, providing a promising target for future therapies (119). Additionally, signaling pathway targets can be used as monitoring indicators for studying resistance mechanisms and adjusting treatment plans; analyzing pathway changes through re-biopsy can reveal resistance mechanisms and guide subsequent treatment. Approximately half of the resistance to first-generation EGFR inhibitors is due to the emergence of the secondary T790M mutation. To address this, the third-generation EGFR inhibitor Osimertinib was developed, which effectively overcomes T790M resistance and has become the standard treatment option after resistance develops (120). Through time-of-flight cytometry, it was found that AXL inhibition can induce JAK1-STAT3 signaling to compensate for the loss of AXL, enhancing the potential for distant metastasis in lung cancer (121). AXL is a member of the TAM receptor family, typically overexpressed in cancers, and has become a potential target for malignant tumors (122). The use of sequencing technology to predict targeted drug targets has formed a set of multi-omics integration strategies. By sequencing the genome, transcriptome and by other omics, key genes related to diseases can be systematically identified, and their potential as drug targets can be evaluated. Advances in targeted drug development have led to new drugs addressing various mutations, enhancing the effectiveness and overcoming the limitations of older treatments. Consequently, precise combination strategies based on molecular typing can significantly enhance anti-tumor effects and reduce drug resistance.

As the first line of defense against the invasion of external pathogenic microorganisms, the antiviral response pathway, in addition to the IFN pathway, The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and retinoic-acid-inducible gene-I (RIG-I)/mitochondrial antiviral signaling protein (MAVS), also play key roles in antiviral innate immunity, belonging to the cellular stress response pathway. The release of viral DNA and tumor cell nuclear DNA can activate the cGAS-STING pathway, subsequently triggering a series of signaling cascades, thereby inducing the production of type I IFNs and initiating adaptive immune responses (123). However, in various cancers, interruption or loss of the cGAS-STING pathway has been observed, which prevents OVs from effectively activating this pathway, resulting in a failure to initiate immune responses (124-126). The development of various STING agonists has shown enhanced stability and efficacy in anti-tumor applications (127-129). Sibal et al (130) found that the STING activator 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) combined with the attenuated HSV-1 strain C-REV could induce a more sustained anti-tumor immune response, but they did not conduct an in-depth analysis of how 2'3'-cGAMP affects the intracellular process dynamics related to viral replication mechanisms (130). The RIG-I/MAVS pathway primarily recognizes viral RNA in the cytoplasm. RIG-I has high affinity for double-stranded (ds)RNA with three phosphates on the 5' end. After binding, it also activates the transcription and expression of type I IFNs and various pro-inflammatory cytokines (131). It was reported that HSV-1 infection induces mitochondrial damage and release of mitochondrial DNA, which can trigger cGAS/STING/interferon regulatory factor 3 and RIG-I-MAVS signaling pathways, suggesting that the RIG-I-MAVS pathway can recognize more than just viral RNA (132). Current research mainly focuses on OVs transforming 'cold' tumors into 'hot' tumors and promoting immune cell infiltration and tumor killing by activating the cGAS-STING and RIG-I/MAVS pathway, generating a strong antitumor immune response, and tumors lacking cGAS or STING expression are more easily infected, thereby enhancing oncolytic activity (133-137). However, if this pathway, which is central to antiviral immunity, is excessively or prematurely activated, it may lead to viral clearance, thereby weakening the direct oncolytic effect of the virus. Precisely regulating the balance between viral replication and immune activation is a major challenge for studying the combined use of OVs and related pathway activators. Furthermore, there are no reports in the literature on whether specific inhibitors exist that can temporarily modulate innate antiviral pathways to allow OV spread without causing systemic immunosuppression, which may become a direction for future research.

When OVs enter the body, their ability to induce a strong anti-tumor immune response is also influenced by another key factor. Previous research has indicated that OVs are swiftly neutralized by antibodies upon entering the body, thereby significantly diminishing their therapeutic efficacy (138,139). To overcome this challenge, researchers have proposed employing vector delivery systems to shield OVs from complement and neutralizing antibodies, thereby enhancing tumor targeting. Polymer coatings (140) and cell-derived nanovesicles (141) has been identified as potential vectors for delivering OVs. Another promising approach involves cell-based drug delivery systems, which provide advantages such as extended drug circulation, improved efficacy, controlled drug release and reduced immunogenicity and cytotoxicity (142). Furthermore, chimeric antigen receptor T-cells have been reported as effective carriers for OVs, offering significant advantages in OV therapy against distant tumors (143). However, the immunosuppressive mechanisms present within the TME may restrict the effectiveness of T cells as OV vectors to tumors that are not classified as immune deserts (144). By contrast, mesenchymal stem cells have been extensively investigated as vectors for various OVs, including oncolytic adenovirus, oncolytic HSV, oncolytic MV and oncolytic reovirus (145). This is attributed to their advantageous properties, such as tumor homing, intrinsic anti-cancer capabilities, protection of OVs from neutralizing antibodies and the ability to deliver viruses to tumor sites via trojan horse strategies (146-148). The development and refinement of targeted delivery systems for OVs substantially mitigate the risk of clearance by the host immune system, thereby addressing some of the challenges associated with combining OVs with molecular targeted therapies and enhancing their anti-tumor efficacy. However, in the development of targeted delivery systems, we must consider not only the immunogenicity of the OVs themselves, but also evaluate whether the delivery system could synergize with the OVs to trigger potential risks such as cytokine storms. Therefore, it is necessary to make a rational selection and modification of the carrier. In addition, efficiently and stably assembling OVs with the delivery system while maintaining the activity of both, and achieving large-scale production at a relatively low cost, remains a significant challenge.

The integration of OVs with molecularly targeted therapies constitutes a promising domain for further exploration. Current research predominantly focuses on preclinical trials, with relatively few studies advancing to clinical trials. This limited progression is likely due to the fact that many viruses do not successfully advance beyond phase I trials (149), which are primarily designed to assess safety and determine appropriate dosing parameters. To date, only 13 viruses have exhibited adequate safety profiles and preliminary clinical success to warrant progression to phase II trials, which are intended to assess clinical efficacy (149). Current methodologies for drug combination exhibit inherent limitations, such as the issue of cumulative toxicity, necessitating further clinical trials to ascertain their safety and efficacy. It is crucial to evaluate the rationale behind these combination strategies and to optimize the use of both the shared and unique properties of the drugs, especially in cases where combinations are ineffective (114). Given that tumor cells frequently develop resistance to monotherapies, employing a combination of diverse therapeutic approaches may partially alleviate this resistance (150-152). However, the potential development of new drug resistance following combination therapy, and the subsequent challenges it may pose to tumor eradication, warrant further rigorous investigation and validation.

The efficacy of JX-594 in combination with sorafenib in HCC mentioned in the aforementioned clinical study above is affected by the order of administration, and priority administration of JX-594 may be superior to sorafenib. The underlying mechanisms may be related to the following factors. Immune 'cold tumors' may be more dependent on OV to preferentially initiate immunity (133-135). As a result, preferential injection of OVs can induce immunogenic death of tumor cells, release tumor-associated antigens, promote DC maturation, T-cell infiltration and cytokine secretion, transform 'cold tumors' into 'hot tumors' and provide a more favorable immune environment for subsequent targeted drugs to exert anti-tumor effects (136,153). Some targeted drugs may inhibit OV replication, so prioritizing OV treatment ensures sufficient viral spread and prevents targeted drugs from weakening its oncolytic effect. When OVs are combined with certain antiangiogenic drugs, which induced reduction in blood supply to tumors may limit delivery of OV (154,155). Conversely, targeted drug pretreatment can promote OV replication by downregulating the IFN signaling pathway, a tumor cell defense mechanism (21,34). The use of immunomodulatory drugs to remove immunosuppressive cells such as Tregs and relieve immunosuppression may improve the efficacy of immunotherapy for OV (37,40,41). IFP is one of the key factors hindering the intratumoral distribution of OVs, and the prior use of chemotherapy drugs such as cyclophosphamide can reduce tumor IFP, further improve the intratumoral distribution of OV, and enhance its oncolytic effect (156). Considering the above factors, based on the dynamic changes of tumor characteristics, viral characteristics, drug mechanism and TME, adjusting the order and dose of drugs can enhance the anti-tumor effect.

OVs and targeted drugs each have their own toxic effects, and when used in combination, careful consideration should be given to whether potential additive toxicity could cause serious adverse events. To date, the combination of therapies mentioned in this study has not yet undergone clinical translation, and the unique toxicities that may arise warrant attention. Protein kinase inhibitors (PKIs) inhibit downstream signaling by targeting specific oncogenic kinases and are one of the research focuses in cancer therapy. However, most analyzed PKI product characteristic summaries and European public assessment reports indicated severe hepatotoxicity (157). Furthermore, the hepatotoxicity caused by OVs themselves also needs to be taken seriously when combined with targeted therapy. Therefore, before treatment, patients at high risk of hepatotoxicity should be identified through relevant biomarkers. In addition, the nonspecific receptor CAR targeted by OVs is also present in normal liver cells (158), and the virus can be genetically engineered to avoid being taken up by the liver or infecting liver cells.

Sunitinib, which is the most involved targeted drug in mechanistic studies, shows a higher prevalence of reduced left ventricular ejection fraction and bone marrow suppression (159). OVs therapy is generally not considered to have significant bone marrow suppression characteristics, and the incidence and severity of hematologic toxicity are usually low. However, certain wild-type OVs, such as oHSV-1, when administered locally to lesions, do not cause viremia, but in rare cases, intravenous administration can lead to a strong systemic immune response due to large-scale viral replication, which may indirectly affect bone marrow function and result in transient cytopenia (160). In addition, bone marrow suppression is also the most common side effect of PARPi (161). Therefore, when considering the combination of sunitinib or PARPi with OVs, the hematological toxicity caused by both should be of concern. The complete blood count should be monitored regularly, and when grade ≥3 toxicity occurs, it is usually necessary to suspend treatment. Once recovery to grade ≤1 is achieved, the dose needs to be reduced upon resuming to avoid irreversible consequences.

Delta-24-RGD is commonly used for intratumoral injection in the treatment of recurrent gliomas, with neurological symptoms being the most common adverse events, such as headaches, speech disorders and cerebral edema (70). ONC201 has shown significant efficacy against certain high-grade gliomas in clinical trials, but it can also lead to adverse events related to the nervous system (162). The therapeutic effect of their combined treatment on tumors is undeniable, but the potential overlapping side effects on the central nervous system should not be overlooked either. Furthermore, distinguishing whether these neurological symptoms are caused by treatment-related inflammation, which may indicate the effectiveness of the treatment, or by the progression of the tumor itself, is crucial in clinical practice and is also a challenge in management. Certain wild-type viruses naturally have neurotropism, and by genetically modifying these viruses, their ability to infect and damage normal nerve cells can be significantly weakened (163-165).

At the same time, the size and location of the tumor, previous treatment history such as radiotherapy that can damage the blood-brain barrier, and pre-existing neurological deficits may all amplify the neurotoxicity of combined therapy (166). Bevacizumab combined with RAMBO can enhance the efficacy against malignant glioma through the CCN1-AKT pathway, but its dual anti-angiogenic effect could significantly increase its impact on the vascular system, excessively suppressing angiogenesis in both the tumor and surrounding normal tissues, leading to tissue ischemia and necrosis (167,168). Therefore, when conducting further clinical research, the optimal order, dosage and interval for administering the two drugs should be determined to balance efficacy and toxicity. In addition, the new genes carried by the genetically engineered recombinant oncolytic viruses may lead to additional side effects. Based on studies of relevant OVs and the toxicity of targeted drugs, future clinical development requires cautious dose exploration and safety management.

In conclusion, the present study collected literature on the mechanisms and clinical research of OVs combined with targeted drugs over the past two decades. There may be potential selection bias, while literature on this research area is relatively sparse and outdated. Additionally, the weighting between preclinical and clinical evidence is uneven and quantitative synthesis of efficacy across studies is limited.