Cancer Must Silence Its Own Viral Alarm to Become Malignant, Review Argues

The journey from a healthy cell to a full-blown tumour is usually described as a story of runaway proliferation: oncogenes switched on, tumour suppressors switched off, growth signals rewired. But a new review in Nature Reviews Cancer argues that this familiar narrative is incomplete, because the very disruptions that drive malignant transformation carry a hidden cost. When cancer-causing changes destabilize the transcriptional and epigenetic controls that normally keep vast stretches of the genome silent, they inadvertently wake up ancient genomic stowaways — transposable elements and other repetitive DNA — whose transcripts can masquerade as viral infection. The result is a phenomenon known as viral mimicry, an intrinsic antiviral alarm that emerging cancer cells must learn to disarm before they can survive. According to the review, authored by Raymond Chen, Aobo He, Håvard T. Lindholm and Daniel D. De Carvalho, escaping this alarm is not merely advantageous for tumours; it is a necessary feature of malignant transformation itself.

Viral mimicry was formally described in 2015, when two landmark studies showed that inhibiting DNA methylation in cancer cells could trigger an interferon response without any actual virus being present. The trigger turned out to be endogenous double-stranded RNA derived from endogenous retroviruses and other repeats that had been derepressed by epigenetic drugs. Since then, a large body of work has mapped how this process works at the molecular level. Many transposable elements, including long interspersed nuclear elements such as LINE1 and short interspersed elements such as Alu, retain vestiges of their viral ancestry, including promoter sequences and the capacity to generate RNA species that form double-stranded structures. Pairs of oppositely oriented Alu elements, known as IR-Alus, can fold into intramolecular double-stranded RNA hairpins that are recognized by innate immune sensors such as MDA5, while PKR and ZBP1 provide additional surveillance routes for endogenous double-stranded RNA and Z-form nucleic acids.

The review emphasizes that viral mimicry is not an accidental by-product confined to drug treatment. Cancer-associated alterations in DNA methylation, histone modifications, splicing and RNA processing routinely generate immunogenic nucleic acids in precancerous cells. Global DNA hypomethylation, a common feature of tumour genomes, relaxes repression at repetitive loci; loss of histone marks such as H3K9me3, mediated by enzymes like SETDB1, or disruption of Polycomb repressive complexes derepresses endogenous retroviruses. Splicing defects, which are pervasive across cancer transcriptomes, can create retained introns and aberrant junctions that form double-stranded RNA or Z-RNA structures sensed by MDA5, PKR and ZBP1. Even mitochondrial double-stranded RNA and cytoplasmic RNA–DNA hybrids derived from R-loops can contribute to the endogenous pool of alarm signals. In this sense, the review argues, the pro-tumorigenic regulatory chaos of transformation is inseparable from the collateral production of viral-like nucleic acids.

Viewed through this lens, viral mimicry emerges as a tumour-suppressive mechanism that shapes tumour evolution from its earliest stages. Cells that activate these antiviral programmes can undergo apoptosis, necroptosis, pyroptosis or translational shutdown driven by PKR, or they can attract immune cells through type I interferon signalling that enhances antigen presentation and cytotoxic lymphocyte activity. Recent work describing viral mimicry as a bottleneck in early cancer evolution, including evidence that the pathway acts as a tumour suppressor in inflammatory contexts such as colitis, supports the idea that most cells attempting transformation are eliminated precisely because they cannot simultaneously disrupt their epigenome and silence the repeats that become exposed. Only clones that acquire effective escape mechanisms survive this selective filter, which is why the review frames viral mimicry escape as a prerequisite rather than an option for malignant cells.

The mechanisms cancer cells use to escape are diverse and, the authors argue, reveal a fundamental dependency. On the transcriptional side, tumours often impose compensatory epigenetic repression on repetitive elements, re-engaging DNA methyltransferases, SETDB1, the RB–EZH2 complex or KDM5B to re-silence retroelements. At the RNA level, the editing enzyme ADAR1 converts adenosine to inosine within double-stranded RNA, destabilizing the structures that immune sensors require and acting as a master regulator of viral mimicry escape; high ADAR1 activity is a hallmark of many tumours and is exploited in leukaemia relapse and other contexts. RNA modifications add another layer: N6-methyladenosine deposited by METTL3 and related machinery can reshape double-stranded RNA to prevent sensor recognition and control the fate of endogenous retroviruses. RNA decay enzymes provide a further escape route, with the exonuclease XRN1 degrading retroelement transcripts, while proteins such as DHX9 and the LINE1 ORF1 protein — which acts like a viral innate immune evasion factor — can chaperone or sequester problematic nucleic acids.

Beyond eliminating the trigger molecules themselves, tumours can dampen the downstream signalling that would translate them into an immune response. Sensor pathways can be epigenetically silenced, as has been described for STING and RIG-I–MAVS components in various cancers; interferon signalling itself can be attenuated through regulators such as USP18 and STAT2, or through negative feedback that blunts the antiviral state. Oncogenic drivers also contribute: mutant KRAS in colorectal cancer impairs DDX60-mediated double-stranded RNA accumulation and viral mimicry, converting immunologically hot tumours into cold ones, while p53 loss has been shown to create chronic viral mimicry pressure that selected clones must overcome. Chemotherapy-resistant breast cancers can switch epigenetic states to evade viral mimicry, illustrating that escape is a dynamic, evolving process throughout tumour progression rather than a one-time event.

The review also connects escape mechanisms to biomarkers and therapeutic vulnerabilities. LINE1 ORF1 protein circulating in the blood has been developed as an ultrasensitive multicancer biomarker, and genome-wide repeat landscapes measurable in cell-free DNA reflect the extent of repeat deregulation in individual tumours. Ratios of stemness to interferon signalling have been proposed as biomarkers of progression in myeloproliferative neoplasms. More importantly, every escape mechanism creates a dependency: tumours that rely on ADAR1, XRN1, DHX9, SETDB1 or m6A machinery to survive their own endogenous viral alarm are theoretically vulnerable to drugs that disable those factors. Pharmacological reactivation of viral mimicry — through DNA methyltransferase inhibitors, EZH2 inhibitors, LSD1 inhibitors, spliceosome-targeted therapies, PRMT inhibition or METTL3 blockade — has been shown in preclinical models to restore immunogenicity, and several such approaches are now entering clinical testing.

Combining viral mimicry induction with immunotherapy is a central translational theme. Because viral mimicry activation enhances antitumour immunity and sensitizes cells to immune checkpoint blockade, epigenetic priming with DNMT inhibitors followed by anti-PD1 therapy has shown promise, including in relapsed or refractory NK/T-cell lymphoma, where one of the first trials demonstrating that triggering viral mimicry could augment checkpoint immunotherapy has now been reported. Similar synergy has been observed with EZH2 inhibition in prostate cancer and glioblastoma models, with ZBP1-driven immunogenicity in HER2-directed combinations, and with strategies that restore cGAS–STING and RIG-I–MAVS signalling. Conversely, the review notes that sustained type I interferon signalling can also mediate resistance to some therapies, underscoring that timing, context and combination design matter when manipulating these pathways in patients.

By gathering this evidence into a single conceptual model, the authors propose a reframing of malignant transformation itself: cancer is not simply uncontrolled growth, but uncontrolled growth that has necessarily survived an internal antiviral insurgency of its own making. This unifying model explains why escape mechanisms are so consistently observed across tumour types, why they map onto established dependencies, and why deliberately reactivating viral mimicry represents a rational strategy to expose tumours to their own genome once again. If the framework holds up under experimental and clinical scrutiny, the ancient viral fossils scattered through human DNA may prove to be one of oncology’s most powerful untapped weapons — an alarm that every successful cancer has had to silence, and that medicine may now learn to ring.

Subject of Research: Viral mimicry escape mechanisms in malignant transformation and cancer immunotherapy

Article Title: Viral mimicry escape as a necessary feature of malignant transformation

Article References: Viral mimicry escape as a necessary feature of malignant transformation. (n.d.). https://doi.org/10.1038/s41568-026-00977-1

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00977-1

Keywords: viral mimicry, transposable elements, malignant transformation, epigenetics, interferon signalling, endogenous retroviruses, ADAR1, immune checkpoint blockade, DNA methylation, cancer immunotherapy, innate immunity, double-stranded RNA