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KDM5 Inhibitors: A Potential Tumor-specific Epigenetic Therapy that Functions through Viral Mimicry

By Stuart P. Atkinson, Ph.D.

January 26, 2026

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The Complex Links Between R-loop Formation, KDM5, and Viral Mimicry in Tumor Cells

The expression of the endogenous, virus-like elements present in considerable numbers in the human genome can lead tumor cells to appear virally infected through the formation of double-stranded RNAs, which trigger a type I interferon response. This process, known as “viral mimicry,” also leads to a decrease in tumor cell fitness and an increase in immunogenicity (Roulois et al., Chiappinelli et al., Chen et al., and Jansz and Faulkner); therefore, tumors may require mutations in type I interferon signaling genes or the implication of viral restriction factors or epigenetic repressive mechanisms to continue to develop and evolve (Chen et al., Vashi and Bakhoum, and Cheon et al.).

DNA methylation epigenetically suppresses the expression of these virus-like elements; however, cancer-associated epigenetic alterations - such as DNA hypomethylation - can prompt their aberrant re-expression (Feinberg and Vogelstein and Ehrlich, 2009), which subsequently impacts cancer evolution and drug resistance. Additionally, inhibitors of histone lysine demethylases (KDMs) (Sheng et al., Wu et al., Zhang et al., Shen et al., and Leadem et al.) can also induce viral mimicry by reactivating these virus-like elements; do these epigenetic pathways represent a potentially targetable anti-tumor mechanism?

The cGAS–STING pathway (cyclic GMP-AMP synthase - stimulator of interferon genes) mediates viral mimicry after pathway activation by RNA:DNA hybrid species such as R-loops (Chen et al. and Mankan et al.). While serving as crucial intermediates in normal cellular processes, R-loops can compromise genomic stability, induce DNA damage, and trigger inflammatory responses by upregulating interferon signaling. Indeed, dysregulation of R-loop formation and the cGAS/STING pathway has been implicated in cancer (Mackay et al. and Cristini et al.), and R-loop formation has been linked to DNA damage and heightened sensitivity to drugs that induce DNA damage (Petropoulos et al., Laspata et al., and Kemiha et al.). Interestingly, studies have revealed that the lysine demethylase 5 family (KDM5A-D), which removes the permissive H3K4me2 and H3K4me3 modifications (Pavlenko et al.), may suppress viral mimicry by repressing STING expression or modifying signaling components downstream of STING (Wu et al., Zhang et al., and Shen et al.).

In a new eLife study, research led by Chames Kermi, Paul Moore, and Marie Classon (Pfizer Center for Therapeutic Innovation, San Francisco), with the help of Brian Egan and Brad Townsley from Active Motif, revealed that KDM5 family members normally suppress R-loop formation at genomic repeat regions such as endogenous, virus-like elements in cancer cells (Lau et al.) and, as such, identified KDM5 inhibitors as potential stand-alone cancer therapies or crucial elements in combination with immune or DNA-damaging cancer therapies that may spare normal cells.

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KDM5 Inhibition Activates Ciral Mimicry in Tumor Cells but Spares Normal Cells

In brief, this new study revealed that the KDM5 demethylases regulated viral mimicry and DNA damage in luminal breast cancer cells. The authors discovered that KDM5 inhibition activated viral mimicry in luminal breast cancer cell lines responsive to STING and increased H3K4me3 levels at repeat regions associated with endogenous virus-like elements, leading to increased R-loop formation and associated DNA damage, which reduced tumor cell fitness independently of type I interferon signaling. Increased levels of R-loops activated the cGAS–STING pathway, leading to increased interferon-stimulated and antigen presentation gene expression and to increased cell-surface major histocompatibility complex class I (MHC I) expression. Of note, reduced surface MHC I levels on tumor cells decrease their intrinsic immunity and limit responsiveness to therapies such as adoptive T cell therapies. Overall, the authors suggest that KDM5 inhibition (and other factors whose disruption or inhibition results in tumor-specific increases in R-loops) may represent a potent anti-tumor therapy or a means to potentiate additional synergistically activating therapeutic approaches, such as DNA damage-promoting drugs or immunotherapies.

Interestingly, the authors also found that KDM5 inhibition did not activate viral mimicry in normal primary breast epithelial cells, with no induction of DNA damage or activation of the CGAS/STING pathway. This encouraging finding situates KDM5 inhibitors as a safer, more amenable therapeutic option for cancer when compared to STING agonists or type I interferons. Furthermore, preliminary data suggest that KDM5 inhibitors have little or no major adverse effects on primary T cells or macrophages and instead induce a potentially more anti-tumorigenic phenotype.

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How Active Motif Can Help Your Research Aims!

This exciting paper helps to broaden appreciation of the links between the chromatin status of virus-like element loci, R-loop formation, innate immunity, and cell fitness during tumor development and highlights KDM5 inhibitors as a safe and promising therapeutic approach, alone or as part of synergistic anti-tumor combinations. The authors hope that future studies will explore the relevance of these findings across other cancer subtypes and report that hematologic cancer cells that are sensitive to KDM5 inhibitors exhibit markers of type I interferon signaling in preliminary studies.

Of note, this exciting study employed a plethora of Active Motif products and services, including the PIXUL Multi-Sample Sonicator, the CUT&Tag-IT Assay Kit, the CUT&Tag-IT R-loop Assay Kit, the CUT&Tag-IT Spike-In Control (Cat. No 53168), the CUT&Tag-IT^® R-loop Spike-In Control, and the primary H3K4me3 antibody.

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

Contact Stuart on X with any questions

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