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Review Open Access

ISG20: The multifaceted ‘molecular star’ in cancer research (Review)

  • Authors:
    • Xinhui Zhu
    • Shihao Jiang
    • Lipeng Zhang
    • Shaojian Zou
    • Houqin Zhang
    • Jingyu Zhang
    • Liyu Chen
    • Hui Li
    • Zhen Zong
  • View Affiliations / Copyright

    Affiliations: Department of Gastrointestinal Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Huan Kui Academy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, The Second Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Rheumatology and Immunology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
    Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 152
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    Published online on: September 11, 2025
       https://doi.org/10.3892/or.2025.8985
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Abstract

IFN‑stimulated gene (ISG)20 is a key member of the ISG family, serving a central role in antiviral defense, immune regulation and cell metabolism through its exonuclease activity. ISG20 is markedly dysregulated in various malignancies, including clear cell renal cell carcinoma, glioma, breast cancer and hepatocellular carcinoma, and it is associated with tumor proliferation, metastasis, angiogenesis and immune evasion. Its dual regulatory roles, such as promoting tumor progression via the MMP9/CCND1 signaling axis or enhancing antitumor immunity by activating the IFN‑β pathway, highlight its complex involvement in tumor biology. The present review aimed to summarize the discovery, structural characteristics and physiological functions of ISG20, and its multifaceted roles in tumor development. Moreover, the potential of ISG20 as a novel biomarker, immunoadjuvant and therapeutic target is discussed, offering theoretical insight and translational directions for precision oncology.
View Figures

Figure 1

Timeline for ISG20/HEM discovery.
ISG, IFN-stimulated gene; HEM, HeLa estrogen-modulated.

Figure 2

Schematic representation of the
structure of ISG20.ISG, IFN-stimulated gene.

Figure 3

Mechanistic pathway of ISG20
antiviral activity. Viral dsRNA is recognized by PRR, activating
NF-κB/IRF1 to upregulate ISG20. ISG20 degrades viral RNA and
activates RIG-I/MAVS for IFN production. IFN-induced IFIT1 binds
viral RNA, inhibiting replication and viral-PRR interaction. Viral
RNA fragments modulate the response, forming a coordinated innate
immune network. ISG, IFN-stimulated gene; IFIT, Interferon-induced
protein with tetratricopeptide repeats; IRF, IFN regulatory factor;
PRR, Pattern recognition receptor; ds, double-stranded; RIG-I,
Retinoic Acid-Inducible Gene I; MAVS, Mitochondrial Antiviral
Signaling Protein.

Figure 4

Mechanism of ISG20 in promoting tumor
cell proliferation, migration, invasion and angiogenesis. ISG20,
induced by thyroid hormone, promotes cancer cell proliferation,
migration, invasion and angiogenesis. It acts via pathways like
CCND1/MMP9 for proliferation, ECM-degrading enzymes for
migration/invasion, and IL-8-JAK2/STAT3-VEGF for angiogenesis. ISG,
IFN-stimulated gene; CCND, cyclin D1; P, phosphorylation.

Figure 5

ISG20 is up- or downregulated in
different cancers. ISG, IFN-stimulated gene.

Figure 6

Mechanism of ISG20 regulating tumor
immune microenvironment. In ovarian cancer, ISG20 degrades dsRNA
into fragments, activating RIG-I/MAVS to induce IFN-β, which
recruits CD8+ T cells and enhances immunogenicity. In
other cancers, ISG20 upregulates CCL-2/5, recruiting
monocyte-derived macrophages/neutrophils, reducing T cells and
forming an immunosuppressive tumor microenvironment. ISG,
IFN-stimulated gene; ds, double-stranded; RIG-I, retinoic
Acid-Inducible Gene I; MAVS, Mitochondrial Antiviral Signaling
Protein.
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Copy and paste a formatted citation
Spandidos Publications style
Zhu X, Jiang S, Zhang L, Zou S, Zhang H, Zhang J, Chen L, Li H and Zong Z: ISG20: The multifaceted ‘molecular star’ in cancer research (Review). Oncol Rep 54: 152, 2025.
APA
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J. ... Zong, Z. (2025). ISG20: The multifaceted ‘molecular star’ in cancer research (Review). Oncology Reports, 54, 152. https://doi.org/10.3892/or.2025.8985
MLA
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J., Chen, L., Li, H., Zong, Z."ISG20: The multifaceted ‘molecular star’ in cancer research (Review)". Oncology Reports 54.5 (2025): 152.
Chicago
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J., Chen, L., Li, H., Zong, Z."ISG20: The multifaceted ‘molecular star’ in cancer research (Review)". Oncology Reports 54, no. 5 (2025): 152. https://doi.org/10.3892/or.2025.8985
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu X, Jiang S, Zhang L, Zou S, Zhang H, Zhang J, Chen L, Li H and Zong Z: ISG20: The multifaceted ‘molecular star’ in cancer research (Review). Oncol Rep 54: 152, 2025.
APA
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J. ... Zong, Z. (2025). ISG20: The multifaceted ‘molecular star’ in cancer research (Review). Oncology Reports, 54, 152. https://doi.org/10.3892/or.2025.8985
MLA
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J., Chen, L., Li, H., Zong, Z."ISG20: The multifaceted ‘molecular star’ in cancer research (Review)". Oncology Reports 54.5 (2025): 152.
Chicago
Zhu, X., Jiang, S., Zhang, L., Zou, S., Zhang, H., Zhang, J., Chen, L., Li, H., Zong, Z."ISG20: The multifaceted ‘molecular star’ in cancer research (Review)". Oncology Reports 54, no. 5 (2025): 152. https://doi.org/10.3892/or.2025.8985
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