Inhibition of METTL3 by STC-15 induces RNA misprocessing that results in dsRNA formation and activates innate immunity [RNA-Seq MC38]

Following loss of m6A, we uncovered aberrant mRNA transcripts arising from intron retention (IR) and transcriptional run-on (RO) events downstream of m6A-enriched exons in human cancer cells and in tumour samples in vivo. We found that these IR and RO events produce double-stranded RNA and are bound by the cytoplasmic dsRNA sensor MDA5.Using preclinical in vitro and in vivo models, we characterised in detail the anti-tumour immune responses induced by STC-15.

Our study reveals how METTL3 inhibition leads to dsRNA accumulation, which triggers a type I interferon response and induces anti-tumour immunity. Together, these findings provide a mechanistic rationale for STC-15 as a novel anti-cancer drug both as monotherapy and in combination with anti-PD1 checkpoint inhibitors.