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Background <p>People with triple-negative breast cancer (TNBC) typically have poorer survival than those with other breast cancer subtypes, with fewer treatment options available. Type I interferon (IFN) signaling has been reported as an important regulator of metastasis and therapeutic response in TNBC, but the off-target toxicity of IFN therapies has limited progression to clinical use. Augmenting Bone Morphogenetic Protein (BMP) signaling has also been associated with anti-metastatic effects, but BMP therapies are not clinically available presently. Tilorone is an anti-viral drug that induces IFN signaling, which has recently gained added attention as an enhancer of BMP signaling. As an agent capable of enhancing two mechanisms of interest, we therefore aimed to test the therapeutic effects of tilorone in preclinical models of metastatic breast cancer.</p> Methods <p>The effect of tilorone on 4T1.2, EMT6.5, TBCP-1 and MDA-MB-231-HM cells was studied using multiple <i>in vitro</i> assays. We also compared metastatic burden by qPCR in mice bearing orthotopic 4T1.2 mammary tumors – a syngeneic and metastatic model of TNBC – with and without tilorone by unpaired t-tests. The effect of tilorone in combination with 4&#xa0;mg/kg doxorubicin was tested by a 2-way ANOVA.</p> Results <p>In 4T1.2 cells, tilorone increased expression of IFN stimulated genes (ISGs). Tilorone also reduced lung metastatic burden. Improvements in survival associated with tilorone administration were blunted in mice that lacked the IFNα/β receptor (IFNAR1). The anti-metastatic impact of tilorone was further examined in combination with doxorubicin. In mice bearing 4T1.2 tumors, and receiving doxorubicin, co-treatment with tilorone increased natural killer (NK) cell maturation in the primary tumor, increased CD4<sup>+</sup> &amp; CD8<sup>+</sup> T cell activation and NK cell maturation in the pre-metastatic lung, and enhanced metastasis-free survival. Analysis of patient data identified high ISG gene expression in tumors correlated with increased overall survival in TNBC but not in patients with other breast cancer subtypes. Additionally, most ISGs were more highly expressed in the tumors of TNBC patients who responded to chemotherapy, compared to non-responders.</p> Conclusions <p>Collectively, the data support the utility of tilorone and other inducers of IFN signaling to enhance the effects of chemotherapeutic drugs for treating metastatic breast cancers.</p>

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Reduction of primary tumor growth and metastasis in models of triple-negative breast cancer following tilorone administration via type I interferon signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月7日

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  • Alastair A. E. Saunders,
  • Kellie A. Mouchemore,
  • Laura Vojtech,
  • Lauren S. James,
  • Thomas B. Chadwick,
  • Lap Hing Chi,
  • Chris Karagiannis,
  • Caroline Bell,
  • Rachel E. Thomson,
  • Belinda S. Parker,
  • Robin L. Anderson,
  • Paul Gregorevic

摘要

Background

People with triple-negative breast cancer (TNBC) typically have poorer survival than those with other breast cancer subtypes, with fewer treatment options available. Type I interferon (IFN) signaling has been reported as an important regulator of metastasis and therapeutic response in TNBC, but the off-target toxicity of IFN therapies has limited progression to clinical use. Augmenting Bone Morphogenetic Protein (BMP) signaling has also been associated with anti-metastatic effects, but BMP therapies are not clinically available presently. Tilorone is an anti-viral drug that induces IFN signaling, which has recently gained added attention as an enhancer of BMP signaling. As an agent capable of enhancing two mechanisms of interest, we therefore aimed to test the therapeutic effects of tilorone in preclinical models of metastatic breast cancer.

Methods

The effect of tilorone on 4T1.2, EMT6.5, TBCP-1 and MDA-MB-231-HM cells was studied using multiple in vitro assays. We also compared metastatic burden by qPCR in mice bearing orthotopic 4T1.2 mammary tumors – a syngeneic and metastatic model of TNBC – with and without tilorone by unpaired t-tests. The effect of tilorone in combination with 4 mg/kg doxorubicin was tested by a 2-way ANOVA.

Results

In 4T1.2 cells, tilorone increased expression of IFN stimulated genes (ISGs). Tilorone also reduced lung metastatic burden. Improvements in survival associated with tilorone administration were blunted in mice that lacked the IFNα/β receptor (IFNAR1). The anti-metastatic impact of tilorone was further examined in combination with doxorubicin. In mice bearing 4T1.2 tumors, and receiving doxorubicin, co-treatment with tilorone increased natural killer (NK) cell maturation in the primary tumor, increased CD4+ & CD8+ T cell activation and NK cell maturation in the pre-metastatic lung, and enhanced metastasis-free survival. Analysis of patient data identified high ISG gene expression in tumors correlated with increased overall survival in TNBC but not in patients with other breast cancer subtypes. Additionally, most ISGs were more highly expressed in the tumors of TNBC patients who responded to chemotherapy, compared to non-responders.

Conclusions

Collectively, the data support the utility of tilorone and other inducers of IFN signaling to enhance the effects of chemotherapeutic drugs for treating metastatic breast cancers.