m6A modification suppresses innate anti-tumour immunity in colorectal cancer by limiting alu-derived dsRNA accumulation

Abstract How cancer cells evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts remains unclear. In cancer, endogenous REs that escape epigenetic silencing are transcribed and can form double-stranded RNA (dsRNA), which activates innate immune responses through viral mimicry. However, RNA-level mechanisms can limit this effect. Here we show that the m 6 A RNA methyltransferase METTL3 acts as a key regulator of this suppression in colorectal cancer (CRC). Targeting METTL3 increases the accumulation of dsRNAs derived from both pre-existing and newly transcribed REs, amplifying immunostimulatory signalling and activating cell-intrinsic anti-tumour immunity. CRCs display variable sensitivity to METTL3 inhibition: tumours with high basal dsRNA and RNA methylation respond to METTL3 blockade alone, whereas those with low RNA methylation require combination therapy. Co-treatment with DNA methyltransferase inhibitors (DNMTis) restores immune activation in resistant tumours. Together, our findings identify METTL3 as an RNA-level immune checkpoint and suggest combined METTL3 and DNMT inhibition as a therapeutic strategy in CRC.