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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-1\u03b1 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.<\/jats:p>","DOI":"10.1084\/jem.20250777","type":"journal-article","created":{"date-parts":[[2025,10,25]],"date-time":"2025-10-25T06:20:56Z","timestamp":1761373256000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["HIF-1\u2013mediated ISG20 expression promotes breast cancer stemness and immune evasion"],"prefix":"10.1084","volume":"223","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0333-7712","authenticated-orcid":true,"given":"Yongkang","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Armstrong Oxygen Biology Research Center and Institute for Cell Engineering, Johns Hopkins University School of Medicine 1 , Baltimore, 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