Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors.

三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，预后最差，有效治疗方法很少。在这里，我们鉴定了 MS023，一种 I 型蛋白精氨酸甲基转移酶 (PRMT) 抑制剂，在 TNBC 中具有抗肿瘤生长活性。TNBC 细胞系的通路分析表明，MS023 治疗前后干扰素反应的激活是功能性生物标志物和反应的决定因素，这些观察结果延伸到一组人源类器官。抑制 I 型 PRMT 通过抗病毒防御途径触发干扰素反应，诱导双链 RNA，该双链 RNA 至少部分来源于反向重复 Alu 元件。一起，