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

How cancer cells evade immune detection despite expressing immunostimulatory retroelement (RE) transcripts remains an open question in tumour immunology. 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. Co-treatment with DNA methyltransferase inhibitors (DNMTis) restores immune activation in these otherwise resistant tumours. Together, these findings uncover a novel mechanism by which METTL3 functions as an RNA-level immune checkpoint and suggest that combining METTL3 and DNMT inhibition may overcome resistance and serve as an effective therapeutic strategy in CRC.