SMG6-dependent nonsense-mediated decay maintains dsRNA homeostasis and suppresses immunogenic transcripts in a hepatocellular carcinoma model

The nonsense-mediated mRNA decay (NMD) pathway degrades transcripts bearing premature termination codons (PTCs), typically arising from mutations and RNA processing errors, to prevent the accumulation of aberrant proteins. Its role in cancer is complex, with both tumor-promoting and tumor-suppressive functions described. Here, we selectively inhibit NMD in the liver by conditionally inactivating its endonuclease SMG6 in a genetic mouse model of hepatocellular carcinoma. SMG6 inactivation completely abrogates tumor formation and elicits both innate and adaptive immune responses. Mechanistically, SMG6 deficiency activates the type I interferon response via the double-stranded RNA (dsRNA) sensor MDA5, uncovering a physiological role for NMD in regulating cytoplasmic dsRNA levels. In parallel, stabilization and translation of NMD-target transcripts generate non-canonical immunopeptides presented by MHC-I, promoting potent CD8 ⁺ T-cell responses. These findings establish SMG6-dependent NMD as a core orchestrator of immune tolerance in cancer and reveal that its selective inhibition in cancer cells unleashes immunogenic transcript expression with therapeutic potential.