Huang Wenjun, Zhu Qingyun, Shi Zhichao, Tu Yao, Li Qinyuan, Zheng Wenwen, Yuan Zigao, Li Lulu, Zu Xuyu, Hao Yue, Chu Bizhu, Jiang Yuyang
School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China.
Cell Death Discov. 2024 Mar 15;10(1):143. doi: 10.1038/s41420-024-01895-7.
The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo. Mechanistically, 15a induces a viral mimicry response by promoting the expression of endogenous retroviral elements in breast cancer cells, thus increasing the intracellular level of double-stranded RNA to activate the RIG-I-MAVS pathway. This in turn promotes the production of interferons and chemokines and augments the expression of interferon-stimulated genes and PD-L1. The combination of 15a and an anti-PD-L1 antibody had an additive effect in vivo. These findings indicate that this DNMT/HDACi has immunomodulatory functions and enhances the effectiveness of immune checkpoint blockade therapy. A novel dual DNMT and HDAC inhibitor induces viral mimicry, which induces the accumulation of dsRNA to activate tumoral IFN signalling and cytokine production to enhance the immune response in breast cancer.
现有的乳腺癌传统治疗方法，包括免疫检查点阻断，在某些癌症中效果有限，尤其是三阴性乳腺癌。表观遗传改变，特别是DNA甲基转移酶（DNMT）和组蛋白去乙酰化酶（HDAC）的改变，与乳腺癌发病机制有关。我们证明了DNMT和HDAC在乳腺癌中过表达且呈正相关。DNMT和HDAC抑制剂的联合使用已显示出协同抗肿瘤作用，我们之前设计的双DNMT和HDAC抑制剂（称为DNMT/HDACi）15a在体外和体内均能有效抑制乳腺癌细胞的增殖、迁移和侵袭并诱导细胞凋亡。从机制上讲，15a通过促进乳腺癌细胞中内源性逆转录病毒元件的表达诱导病毒模拟反应，从而增加细胞内双链RNA水平以激活视黄酸诱导基因I（RIG-I）-线粒体抗病毒信号蛋白（MAVS）途径。这反过来促进干扰素和趋化因子的产生，并增强干扰素刺激基因和程序性死亡配体1（PD-L1）的表达。15a与抗PD-L1抗体联合在体内具有相加作用。这些发现表明这种DNMT/HDACi具有免疫调节功能，并增强了免疫检查点阻断疗法的有效性。一种新型双DNMT和HDAC抑制剂诱导病毒模拟，从而诱导双链RNA积累以激活肿瘤干扰素信号和细胞因子产生，增强乳腺癌的免疫反应。
