Effect of depletion of ISG20 on gene expression in EMT6 mouse breast cancer cells with RNA-Seq.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the highest rates of recurrence, metastasis and patient mortality due to lack of effective targeted therapies. In this study, we demonstrate that ISG20 expression is induced by hypoxia and directly targeted by HIF-1 for transcription in TNBC cells. ISG20 functions as RNA exonuclease to target mRNAs for degradation, resulting in breast cancer stem cell specification and lung metastasis, and also cancer cell immune evasion. Mostly importantly, ISG20 silencing could markedly increase the sensitivity of TNBC to anti-PD1 immune checkpoint blockade (ICB) in a mouse model. Our data suggested that, in combination with immunotherapy, targeting ISG20 might be an effective strategy for TNBC treatment.