By showing NMD simultaneously suppresses MDA5-driven innate immunity and neoantigen generation, this work overturns its framing as mere transcript quality control, recasting it as a master immunological checkpoint exploitable for cancer immunotherapy.
We reveal that the RNA decay factor SMG6 plays a central role in suppressing endogenous dsRNA accumulation, thereby preventing the emergence of immunogenic transcripts and limiting hepatocellular carcinoma in vivo. This establishes RNA surveillance as a key determinant of transcriptome integrity with direct relevance for cancer.
Selective inactivation of the NMD endonuclease SMG6 in hepatocytes completely prevents tumor formation in a genetic hepatocellular carcinoma model by simultaneously activating innate immunity through MDA5-mediated sensing of accumulated dsRNA-forming intron-retaining transcripts and adaptive immunity through MHC-I presentation of non-canonical immunopeptides translated from stabilized NMD-target transcripts, establishing SMG6-dependent NMD as a dual gatekeeper that maintains immune tolerance by suppressing both immunostimulatory RNA accumulation and neoantigen expression in cancer.
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.