m6A Methylation Suppresses anti-tumour immune responses in Colorectal Cancers by Inhibiting Double-stranded RNA accumulation from Alu Repeats [MeRIP]

In cancer cells, endogenous REs that escape histone and DNA silencing are transcribed into RNA and can form double-stranded RNA (dsRNA), triggering innate immune responses through a process known as viral mimicry. However, RNA-level checkpoints can limit this effect.

Here, we identify the m6A RNA methyltransferase METTL3 as a key regulator of this suppression in colorectal cancer (CRC). Targeting METTL3 enhances the accumulation of dsRNA derived from both pre-existing and newly transcribed REs, thereby amplifying immunostimulatory signalling and activating cell-intrinsic anti-tumour immunity. Notably, CRCs exhibit differential sensitivity to METTL3 inhibition: tumours with high basal dsRNA levels and RNA methylation respond robustly to METTL3 blockade alone, whereas those with low endogenous dsRNA require combination therapy to achieve comparable immune activation.