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Review Open Access

Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review)

  • Authors:
    • Shiwen Bi
    • Tiyan Shan
    • Yong Tang
    • Qi Wang
  • View Affiliations / Copyright

    Affiliations: Department of Experimental Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi 530021, P.R. China, University Engineering Research Center of Oncolytic & Nanosystem Development, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
    Copyright: © Bi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 25
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    Published online on: December 16, 2025
       https://doi.org/10.3892/ijo.2025.5838
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Abstract

Oncolytic virotherapy has emerged as a significant advancement in cancer treatment. However, the efficacy of monotherapies is limited by tumor heterogeneity, highlighting the need for combination strategies to overcome therapeutic limitations. This study provides a review of the molecular mechanisms, preclinical advancements and clinical outcomes associated with oncolytic virus (OV)‑targeted drug combinations over the past two decades, elaborating on the interaction mechanisms through which molecular targeted drugs and oncolytic viruses enhance antitumor effects. Additionally, the progress in translating OV‑based combination therapies for solid tumors into clinical practice is outlined and innovative strategies are proposed for developing novel therapeutic frameworks.
View Figures

Figure 1

Schematic depicting the main
mechanism. The left panel mainly focuses on the mechanisms by which
tumor cells interact with signaling pathways and DNA damage.
Trametinib combined with oHSV inhibits STAT1, thereby affecting the
type I interferon-mediated antiviral response pathway; Ruxolitinib
promotes VSV replication by inhibiting JAK1/2; MEK inhibitors
promote OVV replication by inhibiting STAT3 phosphorylation;
Axitinib combined with G47Δ-mIL12 inhibits p-AKT and p-ERK to exert
anti-tumor effects; RAMBO increases tumor sensitivity to
bevacizumab by inhibiting CCN1 expression. Olaparib combined with
rMV-Hu191 enhances DNA damage by increasing ROS levels; Olaparib
combined with dl922-947 exacerbates DNA damage to exert anti-tumor
effects. Bortezomib promotes oHSV-1 replication by increasing UPR
accumulation and enhancing HSP90 expression. The right panel mainly
describes the mechanism of action of combinations in the tumor
immune microenvironment. Trametinib mitigates the reduction of oHSV
induced by the exogenous phagocytosis pathway through the
inhibition of TNF-α secretion by macrophages; OV-Cmab-CCL5 enhances
the engagement of Fcγ receptors on the surfaces of macrophages and
NK cells by EGFR tumor cells, thereby facilitating ADCP and ADCC;
the combination of reovirus with sunitinib has been shown to
decrease IFN-γ secretion and reduce the presence of Treg and MDSC
within immunosuppressive environments. The co-administration of
H-1PV with sunitinib significantly augments immune stimulation by
promoting DC maturation, IL-6 release, and the activation of
cytotoxic T lymphocytes. NSCs-OV combined with paquinimod enhances
anti-tumor efficacy by increasing T cell infiltration and reducing
MDSCs. IFN-γ, interferon γ; RAMBO, Rapid antiangiogenesis mediated
by oncolytic virus; CCN1, Cysteine-rich 61; IFN-α, interferon α;
IFN-β, interferon β; JAK, janus kinase; STAT, signal transducer and
activator of transcription; TYK, tyrosine kinase; IRF9, interferon
regulatory factor 9; VSV, vesicular stomatitis virus; MEK,
mitogen-activated protein; OVV, oncolytic vaccinia virus; PI3K,
phosphatidylinositol 3-kinase; PDGFR, platelet-derived growth
factor receptor; ERK, extracellular regulated protein kinases; UPR,
unfolded protein response; HSP90, heat-shock protein 90; HSV,
herpes simplex virus; ROS, reactive oxygen species; IL-6,
interleukin 6; MDSC, myeloid-derived suppressor cell; Treg,
Regulatory T cell; ADCC, Antibody dependent cell-mediated
cytotoxicity; ADCP, Antibody-dependent cell-mediated phagocytosis;
H-1PV, H-1 parvovirus; NSC, neural stem cell; Cmab, cetuximab;
CCL5, C-C motif chemokine ligand 5; TNF, tumor-necrosis factor; NK,
natural killer; DC, Dendritic Cell.

Figure 2

Clinical translation roadmap. In
preclinical studies, in vitro experiments provide guidance
on tumor type choice for patient selection in clinical trial
design, and further help set appropriate recommended endpoints
according to different stages of the trial. Mechanistic exploration
suggests possible combination strategies, and the combined efficacy
in animal models provides references for drug dosage and
administration sequence. Potential toxicities in these three areas
indicate the need for safety monitoring to avoid adverse
events.
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Spandidos Publications style
Bi S, Shan T, Tang Y and Wang Q: Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review). Int J Oncol 68: 25, 2026.
APA
Bi, S., Shan, T., Tang, Y., & Wang, Q. (2026). Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review). International Journal of Oncology, 68, 25. https://doi.org/10.3892/ijo.2025.5838
MLA
Bi, S., Shan, T., Tang, Y., Wang, Q."Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review)". International Journal of Oncology 68.2 (2026): 25.
Chicago
Bi, S., Shan, T., Tang, Y., Wang, Q."Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review)". International Journal of Oncology 68, no. 2 (2026): 25. https://doi.org/10.3892/ijo.2025.5838
Copy and paste a formatted citation
x
Spandidos Publications style
Bi S, Shan T, Tang Y and Wang Q: Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review). Int J Oncol 68: 25, 2026.
APA
Bi, S., Shan, T., Tang, Y., & Wang, Q. (2026). Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review). International Journal of Oncology, 68, 25. https://doi.org/10.3892/ijo.2025.5838
MLA
Bi, S., Shan, T., Tang, Y., Wang, Q."Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review)". International Journal of Oncology 68.2 (2026): 25.
Chicago
Bi, S., Shan, T., Tang, Y., Wang, Q."Advancements on the synergistic application of oncolytic viruses and molecularly targeted therapies for the treatment of solid tumors (Review)". International Journal of Oncology 68, no. 2 (2026): 25. https://doi.org/10.3892/ijo.2025.5838
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