Nonsense-mediated mRNA decay: friend or foe in cancer biology?

Nonsense-mediated mRNA decay (NMD) is a highly conserved RNA surveillance mechanism in eukaryotic cells. It plays a key role in safeguarding the accuracy of gene expression by eliminating mRNAs with premature termination codons (PTCs) in the cellular transcriptome. Furthermore, NMD fine-tunes gene expression by regulating the stability of numerous transcripts that harbor NMD-inducing features other than PTC. Emerging evidence has established NMD factors as key regulators in diverse biological processes, including embryonic development, tissue homeostasis, and tumor biology. This review focuses on the dual roles of NMD in tumorigenesis, cancer therapy, and their underlying mechanisms. NMD can promote tumorigenesis and progression by degrading PTC-containing mRNA variants arising from mutated tumor suppressor genes or by suppressing neoantigen expression. Conversely, NMD can exert tumor-suppressive effects by eliminating aberrant transcripts of certain oncogenes. The function of NMD in tumor dynamics is highly dependent on multiple factors, including the tumor's genetic background, the expression and mutation status of NMD factors, alternative splicing coupled to NMD (AS-NMD), and the tumor microenvironment. Moreover, we summarize cancer therapeutic strategies targeting NMD, especially NMD inhibitors (e.g., NMDI-1, NMDI-14, and 5-azacytidine). The synergistic potentials of combining NMD inhibition with nonsense mutation readthrough therapy, immune checkpoint blockade, and chemotherapy in cancer therapy are summarized. Finally, we provide perspectives on future research directions, emphasizing that a deeper understanding of the context-specific mechanisms of NMD in different tumors is crucial for developing precise anti-cancer therapies.