Endogenous retroelements, including retrotransposons, are normally epigenetically silenced. When this repression is lost, they can be transcribed into RNAs containing inverted repeat Alu sequences that fold into double-stranded RNA (dsRNA). These are recognized as viral elements by innate sensors, triggering type I interferon responses—a process known as viral mimicry—which can enhance cell-intrinsic anti-tumor immunity. In a May issue of Nature Communications, researchers led by Ludwig Oxford’s Parinaz Mehdipour, Yucheng Wang and Alice Daddi identified an RNA-level mechanism that suppresses viral mimicry in colorectal cancer (CRC). They demonstrated that the m6A RNA methyltransferase METTL3 limits the accumulation of Alu-derived dsRNA in CRC cells, suppressing innate immune signaling, and that its inhibition activates viral mimicry in a subset of CRCs. CRCs with high basal m6A methylation and the capacity to generate Alu-derived dsRNA responded to METTL3 inhibition alone. Tumors with lower m6A levels, however, required combination treatment with DNA methyltransferase inhibitors (DNMTis), which increase retroelement transcription and dsRNA production. These findings identify METTL3 as an RNA-level immune checkpoint that suppresses viral mimicry in CRC and suggest its inhibition may improve anti-tumor immunity. Combined METTL3 and DNMT inhibition could be a promising therapeutic strategy for CRCs that are otherwise resistant to METTL3 inhibition alone.
m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation
Nature Communications, 2026 May 14