Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses
Open accessAbstract
We show that DNA methyltransferase inhibitors (DNMTis) upregulate immune signaling in cancer through the viral defense pathway. In ovarian cancer (OC), DNMTis trigger cytosolic sensing of double-stranded RNA (dsRNA) causing a type I interferon response and apoptosis. Knocking down dsRNA sensors TLR3 and MAVS reduces this response 2-fold and blocking interferon beta or its receptor abrogates it. Upregulation of hypermethylated endogenous retrovirus (ERV) genes accompanies the response and ERV overexpression activates the response. Basal levels of ERV and viral defense gene expression significantly correlate in primary OC and the latter signature separates primary samples for multiple tumor types from The Cancer Genome Atlas into low versus high expression groups. In melanoma patients treated with an immune checkpoint therapy, high viral defense signature expression in tumors significantly associates with durable clinical response and DNMTi treatment sensitizes to anti-CTLA4 therapy in a pre-clinical melanoma model.
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The IFN-I response could expose tumor cells to surveillance by the immune system.
“The IFN-I response could also expose the tumor cells to surveillance by the immune system96, 97.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [97]
DNA demethylating agents can induce a type I IFN response in cancer cells through de-repression of endogenous retroviruses and activation of the MDA5-MAVS pathway.
“multiple studies have shown that DNA demethylating agents among other epigenetic modulators can induce a type I IFN response in cancer cells through the de-repression of endogenous retroviruses (ERVs) and activation of the MDA5-MAVS pathway38–40.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [38]
DAC treatment could induce expression of retrotransposons normally silenced by DNA methylation, which could augment tumor immunogenicity.
“DAC treatment could induce expression of retrotransposons normally silenced by DNA methylation, which could also augment tumor immunogenicity10–14,99.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [12]
Inactivated typical enhancers in HCC are associated with collagen fibril organization and chemotaxis GO terms and enriched for binding motifs of immune-related TFs, including STAT1.
“inactivated typical enhancers were associated with collagen fibril organization and chemotaxis GO terms and were enriched for binding motifs of immune-related TFs, including STAT1 (Fig. 2a, b)12,13.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [12]
The Results section on DNMT inhibitors and type I interferon signaling reports STAT1 upregulation in ovarian cancer cell lines, but does not analyze inactivated enhancers in HCC. Searches for collagen fibril organization, chemotaxis, and enhancer-binding motifs found no passage addressing the claimed associations. (LLM, conf=0.75)
Experimental — accuracy not yet measuredInhibiting EZH2 activity can either positively or negatively influence tumour-specific immune responses by modulating both tumour immunogenicity and the function of infiltrating T-cells, NK-cells and macrophages.
“inhibiting EZH2 activity can either positively or negatively influence tumour-specific immune responses by modulating both tumour immunogenicity and the function of infiltrating T-cells, NK-cells and macrophages 196 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [196]
DNMT inhibitors are consistently linked to derepression of endogenous retroviral elements and strong type I and type III interferon signaling.
“derepression of endogenous retroviral elements coupled to robust type I and type III IFN signaling”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Chiappinelli et al., 2015
This dual epigenetic targeting may influence additional antiproliferative mechanisms and enhance antitumor immune surveillance.
“Certainly, this dual epigenetic targeting may influence additional antiproliferative mechanisms and further enhance antitumor surveillance by the immune system (Chiappinelli et al., 2015).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Chiappinelli et al., 2015
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Combining Epigenetic and Immunotherapy to Combat Cancer
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Self-citationEndogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma
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Cancer epigenetics: from laboratory studies and clinical trials to precision medicine
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- Authors
- Chiappinelli, K. B., Strissel, P. L., Desrichard, A., Li, H., Henke, C., Akman, B., Hein, A., Rote, N. S., Cope, L. M., Snyder, A., Makarov, V., Buhu, S., Slamon, D. J., Wolchok, J. D., Pardoll, D. M., Beckmann, M. W., Zahnow, C. A., Merghoub, T., Chan, T. A., Baylin, S. B., & Strick, R.
- Affiliations
- Johns Hopkins University (US)
- Universitätsklinikum Erlangen (DE)
- Memorial Sloan Kettering Cancer Center (US)
- Case Western Reserve University (US)
- University of California, Los Angeles (US)
- Corresponding author
- Baylin, Stephen B.
- Strick, Reiner
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 162
- Issue
- 5
- Pages
- 974-986
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4556003
- OpenAlex
- W1953890763
- Cited by
- 2,022
- References
- 94
- Citations by year
- 2026: 193 · 2025: 188 · 2024: 211 · 2023: 209 · 2022: 225 · 2021: 250 · 2020: 184 · 2019: 163 · 2018: 161 · 2017: 133 · 2016: 93 · 2015: 10
- FWCI
- 65.10
- Type
- journal article
- Language
- en
- Update notices
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P50CA058184, CA058184, F32CA183214, P30CA008748)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- hypomethylating agents, DNA methylation, type I interferon response, double-stranded RNA sensing, endogenous retroviruses, ovarian cancer, melanoma, TLR3, MAVS, interferon-beta, apoptosis, immune checkpoint therapy, CTLA-4, tumor immune microenvironment, epigenetic reprogramming
- MeSH terms
- Animals, Azacitidine, Female, Humans, Immunotherapy, Interferon Type I, Lung Neoplasms, Melanoma, Mice, Inbred C57BL, Ovarian Neoplasms, RNA, Double-Stranded, DNA Modification Methylases, DNA Methylation, Endogenous Retroviruses, Cell Line, Tumor, Mice
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