Abstract
Despite advances in colorectal cancer (CRC) treatment, immunotherapy shows limited efficacy due to low immunogenicity. Nonsense-mediated mRNA decay (NMD) prevents the synthesis of potentially detrimental proteins. While targeting NMD has therapeutic potential, its specific effect on CRC remains uncertain. Our research discovered significant NMD activation and upregulated SMG5 expression in CRC. Inhibition of NMD by small interfering RNA (siRNA) targeting SMG5 or NMD inhibitor NMDI14 remodeled tumor microenvironment (TME) by altering innate immune cells and enhancing CD8+ T cells activation. NMD inhibition also activated TBK1 through upregulation of TRAF6, which was targeted by NMD through its elongated 3'-UTR in a non-canonical manner. High SMG5 and low TRAF6 expression are associated with poor immunotherapy response. Inhibiting NMD enhanced the effectiveness of immune checkpoint blockade (ICB) therapy in CRC. By uncovering the biological relevance and translational potential of targeting NMD to reconstruct TME, this study highlights its promise as a treatment strategy for CRC.