m6A Modification Suppresses Anti-Tumor Immunity in Colorectal Cancer via Alu-Derived dsRNA Regulation

A recent study published in Nature Communications reveals that the m6A RNA methyltransferase METTL3 suppresses innate anti-tumor immunity in colorectal cancer (CRC) by limiting the accumulation of double-stranded RNAs (dsRNAs) derived from Alu retroelements. While retroelement transcripts can trigger immune responses through viral mimicry, METTL3 regulates steady-state dsRNA levels to evade detection. The research demonstrates that inhibiting METTL3 increases dsRNA accumulation, thereby amplifying immunostimulatory signaling and activating cell-intrinsic anti-tumor immunity. CRC tumors exhibit variable sensitivity to this inhibition; those with high basal dsRNA and RNA methylation respond to METTL3 blockade alone. Conversely, tumors with low RNA methylation require combination therapy with DNA methyltransferase inhibitors (DNMTis) to restore immune activation. These findings identify METTL3 as a critical RNA-level immune checkpoint and propose a combined therapeutic strategy targeting both METTL3 and DNMTs to enhance viral mimicry and improve treatment outcomes in colorectal cancer patients.