2. Academic Validation
  3. Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer

Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer

  • Cell Death Discov. 2024 Mar 15;10(1):143. doi: 10.1038/s41420-024-01895-7.
Wenjun Huang 1,  Qingyun Zhu 1 2,  Zhichao Shi 3,  Yao Tu 1,  Qinyuan Li 4,  Wenwen Zheng 1,  Zigao Yuan 4,  Lulu Li 4,  Xuyu Zu 2,  Yue Hao 5,  Bizhu Chu 6,  Yuyang Jiang 7 8 9 10
Affiliations

Affiliations

  • 1 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China.
  • 2 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, China.
  • 3 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
  • 4 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China.
  • 5 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. yuehao@szu.edu.cn.
  • 6 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. chubz@szu.edu.cn.
  • 7 School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, China. jiangyy@sz.tsinghua.edu.cn.
  • 8 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, 518132, China. jiangyy@sz.tsinghua.edu.cn.
  • 9 State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. jiangyy@sz.tsinghua.edu.cn.
  • 10 School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. jiangyy@sz.tsinghua.edu.cn.
PMID: 38490978 DOI: 10.1038/s41420-024-01895-7
Abstract

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.

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