HIF-1–mediated ISG20 expression promotes breast cancer stemness and immune evasion

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis, and patient mortality due to the absence of effective therapies. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of thousands of RNAs in TNBC. Here, we demonstrate that transcription of the ISG20 gene, which encodes an RNA exonuclease, is activated by HIF-1 in TNBC cells. ISG20-mediated degradation of RHOBTB3 mRNA increases HIF-1α protein expression and activates NANOG signaling, which increases breast cancer stem cell specification and lung metastasis. ISG20 also degrades STAT1 and IRF1 mRNAs, leading to decreased expression of CXCL10 and impaired recruitment of CD8+ T cells and natural killer cells, thereby promoting breast cancer immune evasion. Silencing ISG20 increases the sensitivity of mouse TNBC cells to anti-PD1 antibody immune checkpoint blockade. Our data suggest that targeting ISG20, in combination with immunotherapy, could be an effective therapeutic strategy for TNBC.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-10-25
DOI
https://doi.org/10.1084/jem.20250777
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
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article

HIF-1–mediated ISG20 expression promotes breast cancer stemness and immune evasion

Dominic Dordai, Elizabeth E. Wicks, Shaima Salman, Gregg L. Semenza et al.
The Journal of Experimental Medicine
interferon and immune responses
article

HIF-1–mediated ISG20 expression promotes breast cancer stemness and immune evasion

Dominic Dordai, Elizabeth E. Wicks, Shaima Salman, Gregg L. Semenza, Yongkang Yang, Daiana Drehmer, Qiaozhu Zuo, Yajing Lv, Chelsey Chen, Varen Talwar, Yufeng Wang, Tina Huang, Vijay Ramu, Emmanuel Datan
article en

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis, and patient mortality due to the absence of effective therapies. Hypoxia-inducible factor 1 (HIF-1) regulates the expression of thousands of RNAs in TNBC. Here, we demonstrate that transcription of the ISG20 gene, which encodes an RNA exonuclease, is activated by HIF-1 in TNBC cells. ISG20-mediated degradation of RHOBTB3 mRNA increases HIF-1α protein expression and activates NANOG signaling, which increases breast cancer stem cell specification and lung metastasis. ISG20 also degrades STAT1 and IRF1 mRNAs, leading to decreased expression of CXCL10 and impaired recruitment of CD8+ T cells and natural killer cells, thereby promoting breast cancer immune evasion. Silencing ISG20 increases the sensitivity of mouse TNBC cells to anti-PD1 antibody immune checkpoint blockade. Our data suggest that targeting ISG20, in combination with immunotherapy, could be an effective therapeutic strategy for TNBC.

The Journal of Experimental MedicineVol. 223(3)
Johns Hopkins University (US), Johns Hopkins Medicine (US), Renji Hospital (CN), Shanghai Cancer Institute (CN), State Key Laboratory of Oncogene and Related Genes (CN), Sidney Kimmel Comprehensive Cancer Center (US)
Openalex Percentile: Top 54%
interferon and immune responses
DOISourceOpenAlex
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