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Background <p>Oncolytic viruses such as reovirus hold significant promise for cancer therapy, but their efficacy varies across tumor types due to heterogeneous tumor cell sensitivity to reovirus. Elucidating the molecular mechanisms underlying reovirus resistance is therefore critical to improving therapeutic outcomes for resistant tumors.</p> Methods <p>We comprehensively assessed the oncolytic sensitivity of 12 diverse tumor cell lines to reovirus, followed by transcriptomic analysis of two ovarian cancer cell lines with divergent responses. Differentially expressed resistance-associated genes were verified, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway was modulated using the type I interferon (IFN) receptor agonist RO8191 and JAK inhibitor ruxolitinib to evaluate impacts on reovirus replication and oncolysis. Additionally, patient-derived primary breast cancer cells were tested to explore cross-resistance mechanisms between chemotherapy and reovirus.</p> Results <p>Tumor cells were stratified into three groups: high sensitivity (HS, cell viability ≤ 50%), moderate sensitivity (MS, 50–80%), and low sensitivity/resistance (LS, ≥ 80%). Transcriptomic analysis revealed higher baseline IFN-stimulated gene (ISG) expression in reovirus-resistant cells, with 170 ISGs upregulated in LS cells (including 28 interferon-related DNA damage resistance signature (IRDS) genes). ISG overexpression correlated with reovirus resistance: ruxolitinib-mediated JAK-STAT inhibition reduced ISGs and enhanced oncolysis, while pathway activation suppressed reovirus replication. Unphosphorylated ISGF3 (U-ISGF3) may drive IRDS-related ISG expression, contributing to cross-resistance to doxorubicin and reovirus.</p> Conclusions <p>Tumor cell resistance to reovirus is associated with elevated baseline expression of specific ISGs, potentially mediated by U-ISGF3-induced IRDS upregulation. These insights provide a foundation for optimizing reovirus therapy in resistant tumors.</p> Graphical abstract <p></p>

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Reovirus resistance in tumors mediated by elevated ISG expression: overcoming therapeutic resistance via JAK/STAT pathway modulation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Yuxin Yang,
  • Xiaojin Lin,
  • Liang Chen,
  • Yuting Fan,
  • Xiaowei Dou,
  • Jing Zhang,
  • Yingchun Zhang,
  • Dan Liang,
  • Xing Zhao

摘要

Background

Oncolytic viruses such as reovirus hold significant promise for cancer therapy, but their efficacy varies across tumor types due to heterogeneous tumor cell sensitivity to reovirus. Elucidating the molecular mechanisms underlying reovirus resistance is therefore critical to improving therapeutic outcomes for resistant tumors.

Methods

We comprehensively assessed the oncolytic sensitivity of 12 diverse tumor cell lines to reovirus, followed by transcriptomic analysis of two ovarian cancer cell lines with divergent responses. Differentially expressed resistance-associated genes were verified, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway was modulated using the type I interferon (IFN) receptor agonist RO8191 and JAK inhibitor ruxolitinib to evaluate impacts on reovirus replication and oncolysis. Additionally, patient-derived primary breast cancer cells were tested to explore cross-resistance mechanisms between chemotherapy and reovirus.

Results

Tumor cells were stratified into three groups: high sensitivity (HS, cell viability ≤ 50%), moderate sensitivity (MS, 50–80%), and low sensitivity/resistance (LS, ≥ 80%). Transcriptomic analysis revealed higher baseline IFN-stimulated gene (ISG) expression in reovirus-resistant cells, with 170 ISGs upregulated in LS cells (including 28 interferon-related DNA damage resistance signature (IRDS) genes). ISG overexpression correlated with reovirus resistance: ruxolitinib-mediated JAK-STAT inhibition reduced ISGs and enhanced oncolysis, while pathway activation suppressed reovirus replication. Unphosphorylated ISGF3 (U-ISGF3) may drive IRDS-related ISG expression, contributing to cross-resistance to doxorubicin and reovirus.

Conclusions

Tumor cell resistance to reovirus is associated with elevated baseline expression of specific ISGs, potentially mediated by U-ISGF3-induced IRDS upregulation. These insights provide a foundation for optimizing reovirus therapy in resistant tumors.

Graphical abstract