Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6

Nonsense-mediated mRNA decay (NMD) eliminates transcripts with premature termination codons, often resulting from mutations or RNA processing errors. While both pro-and anti-tumor NMD activities have been proposed, mechanistic and therapeutic insights into NMD inhibition in cancer have been hindered by the lack of a suitable in vivo model. We address this by combining a liver-specific, conditional Smg6 mutation – disabling the endonuclease that cleaves NMD-regulated transcripts – with a genetic hepatocellular carcinoma (HCC) model. SMG6 inhibition elevates NMD-sensitive mRNA abundance and translation, promotes MHC presentation of unique immunopeptides, and enhances T-cell infiltration. Additionally, mutant SMG6 specifically activates type-I interferon signaling via double-stranded RNA (dsRNA) accumulation and dsRNA-sensor MDA5, boosting innate immune responses. These pathways converge to halt HCC at an inflammatory stage. Our findings establish SMG6 as a key regulator of dsRNA homeostasis and immune activation, offering therapeutic potential and advancing our understanding of NMD in immune regulation.