Table 2.

Tumor specificity mechanisms of OVs

Mechanism type	Virus	Viral gene and its modification	Viral gene function	Mechanism or target protein	Comments and advantages	Unresolved issues, problems or disadvantages	Refs
Transcriptional targeting	HSV-1	oHSV1-SS1, Signal-Smart 1 (SS1). ICP4 expression under ELK	ICP4, a viral protein necessary for replication	oHSV1-SS1 infects only host cells with overactivation of the Ras/ERK/ELK pathway	SS1 virus preferentially infects prostate cancer cells and induces changes in viability, invasiveness and necrosis	ELK signaling may not reflect the situation in tumor tissues	[165]
Transcriptional targeting	HSV-1	HCC-specific gene promoters	Specific promoters drive selective viral gene expression	Transfer therapeutic genes; target, multiply in, and eradicate hepatoma cells via their lytic cycle	Some HCC-specific gene promoters were identified and can be used for virotherapy	The viral replication relies on the overexpression of B-myb in tumor cells	[11]
Transcriptional targeting	HSV-1	KTR27. The tetR gene controlled by the ICP0 promoter at the ICP0 locus and the essential ICP27 gene under the control of the tetO-bearing ICP27 promoter	ICP0 is required for viral gene expression, replication at low MOI and reactivation; ICP27 is an essential IE protein that modifies and transports viral transcripts to the cytoplasm	Repression of the tetO-bearing ICP27 promoter by tetR would greatly impair the ability of the virus to initiate productive infection in the absence of tetracycline	KTR27 can limit its replication to the targeted TME with localized tetracycline delivery, thus minimizing unwanted viral replication in distant tissues following local virotherapy	Whether KTR27 would be equally effective against small-cell lung cancer or NSCLC xenografts remains to be determined	[166]
Transcriptional targeting	Ad	HYPR-Ad-mIL4, The Ad E1A viral replication and IL-4 genes under the hypoxia/HIF-responsive promoter	Ad E1A makes cells more susceptible to virus replication	Bidirectional tumor-restrictive hypoxia/HIF promoter to drive viral E1A gene expression	Hypoxia-dependent IL-4 expression, viral replication, and conditional cytolysis of hypoxic cells	Limited to tumors that develop hypoxia/HIF activation	[167]
Transcriptional targeting	Ad	Telomelysin (OBP-301); hTERT promoter; combined with chemotherapy drugs: cisplatin and paclitaxel	hTERT promoter to express the viral gene; chemotherapy drugs	Drive the expression of E1A and E1B genes linked with an IRES, induces selective E1 expression, and selectively kills human cancer cells	Most cancer cells express Telomerase transcription factor	These findings need further research in vivo and in different tumor type to determine its validity	[122]
Transcriptional targeting	VV	rVACV is based on the tet operon of transposon Tn10	Tet operon can be activated tetracycline derivatives such as doxycycline	Exogenous control of gene expression levels by administration of a nontoxic inducer	The control of viral gene expression can benefit the safety of virotherapy	Induction rates need increase and the background expression need decrease	[123]
Transductional targeting	VSV	Replication-defective VSV, deleted its glycoprotein gene, VSVΔG, pseudotyped with MV-F and MV-H displaying scFv specific for EGFR, FR or PSMA	VSV G gene encoding VSV-G protein, for cell entry	The retargeted VSV (VSVΔG pseudotypes) infected only cells that expressed the targeted receptors (EGFR, FR, or PSMA)	Pseudotyped VSV infects only cells expressing the corresponding receptor both in vitro and in vivo	The prevalence of preexisting anti-measles antibodies in the patient population could neutralize the systemically administered virus	[168]
Transductional targeting	HSV	scFv-HER2-gH	gH/gL and gB constitute the conserved fusion apparatus	Engineering in gH of scFv directed to the cancer-specific HER2 receptor	Entry of viruses in the absence of gD or upon deletion of key residues in gD for the nectin1/HVEM binding	It can only be used for the tumor cells with HER2 receptor	[14]
Transductional targeting	HSV	gB-scFv-HER2	gB contributes to determine the virus tropism	Engineering in gB of scFv directed to the cancer-specific HER2	Activation of the chimeric gB-HER2 did not require the activation of the gD and gH/gL	Re-targeted to the HER2-positive cancer cells	[169]
Transductional targeting	HSV	gD-GCN4R and gD-HER2	Determine the virus tropism	Simultaneous insertion of both the GCN4 peptide and the Her2 scFv in gD	Re-targeted to the HER2 and GCN4R positive cells	Restricted to HER2 and GCN4R positive cells	[54]
Transductional targeting	HSV	gB-GCN4R and gD-HER2	Determine the virus tropism	Insertion of the GCN4 peptide in gB and detargeting plus HER2-retargeting via gD	Optimize the retargeted oncolytic HSVs to the translational phase	Restricted to the HER2 and GCN4R positive cells	[53]
Transductional targeting	SVV	Wild type virus	Anthrax toxin receptor 1 (ANTXR1)	SVV interacts directly and specifically with ANTXR1	ANTXR1 as the high-affinity cellular receptor for SVV	Non-modified virus	[170, 171]
Immune evasion	HSV-2	Δ ICP47 and ΔICP34.5	ICP34.5, a neurovirulence gene; ICP47 blocks MHC I function in infected cells	Δ ICP34.5 restricts oHSV replication to tumor cells and Δ ICP47 to promote virus oncolytic activity by up-regulating US11 and TAA presentation	Treatment with DOX followed by the oHSV2 was significantly more beneficial than treatment with either agent alone	The extracellular matrix restricts the initial distribution and subsequent spread of viruses in the tumor mass	[55]
Immune evasion	ZIKV	ZIKV-E218A, NS5 (E218A)	NS5 (E218A) has 2'-O methyltransferase activity	ZIKV-E218A sensitizes the virus to translational inhibition by type I IFN and IFIT1	Lysis of glioblastoma stem cells (GSCs) with less toxicity to normal neural cells	The anti-tumor effect remains to be determined n patient-derived GSCs in vivo	[172]
Immune stimulation	NDV	NDV-expressing ICOS ligand (NDV-ICOSL)	Enhance systemic immune checkpoint blockade	NDV-ICOSL enhances tumor control, TIL infiltration, the efficacy of CTLA-4 blockades	Potentially avoiding additional systemic toxicity	ICOSL could have additional interaction partners	[108]
Immune stimulation	Ad	a 24-base-pair deletion in the E1A gene (Ad5D24)	E1A makes cells more susceptible to virus replication	Ad coated with MHC-I tumor epitopes (the modified poly-K-SIINFEKL, PeptiCRAd)	significantly improve the response rate to checkpoint blocking antibodies		[78]
Post-transcriptional targeting	Ad	Insertion of CPE regulatory sequences in the 3’-UTR of the E1A gene (AdCPE)	E1A makes cells more susceptible to virus replication	CPEB4 bind to CPEs in the 3’-UTR of E1A confers E1A expression post-transcriptionally, resulted in tumour-specific oHSV	CPEB-dependent regulation can be exploited to attenuate viral toxicity, by preventing the spread of the virus in normal tissues	Rely on the cellular transcription machinery, but not for viruses that use virally encoded polymerases in the cytoplasm, such as the MV and VV	[56]
miRNA targeting	VSV	4 tandem copies of a neuronal miRNA125 target sequence inserted in the 3’-untranslated region of the viral polymerase (L) gene	Polymerase L gene coding for RNA-dependent RNA polymerase	miRNA125 targets engineered into VSV to ameliorate its neuropathogenicity by restricting viral replication in specific tissues	Compared to picornaviruses and adenoviruses, the VSVs were relatively resistant to miRNA-mediated inhibition, but neurotoxicity was ameliorated significantly	Mutation and selection of viruses containing altered miRNA target sequences could be a potential pitfall, with mutations in the miRT sequence reducing the efficiency	[57]
miRNA targeting	HSV	apoE-AAT promoter linking with gH and miR-122a complimentary sequence at 3’UTR of gH (LCSOV)	gH is needed for virus assembly and cell entry	Viral gene are replicatible in HCC owning to absent of miR-122a	LCSOV is a safe oHSV that can precisely target HCC both in vivo and in vitro	The strategy depends heavily on promoter activity in the targeted tumor cells	[12]
Translational targeting	HSV-1	ICP6 expression is defective, and expression of the HSV-1 γ1 34.5 gene is regulated by the cellular B-myb promoter (Myb34.5)	The UL39 gene encodes ICP6, an ICP6 mutant HSV that can only replicate in dividing cells	oHSV γ1 34.5 kills tumor cells by PKR-induced inhibition of cell proliferation and tumor growth; ICP6 defective oHSV efficiently replicates and kills dividing cells	HSV-1-based selective Myb.34.5 virus effectively replicates and kills PDAC-derived cells both in vitro and in vivo	The viral replication relies on the overexpression of B-myb in tumor	[13]