Nonsense-mediated mRNA decay as a gatekeeper of neoantigen expression: Bridging RNA surveillance and tumor immunotherapy.

The nonsense-mediated mRNA decay (NMD) is a highly conserved post-transcriptional mRNA screening system that is vital in keeping cellular integrity by targeting aberrant mRNAs harboring premature termination codons (PTCs) for degradation. Although traditionally considered as a system of RNA quality control, NMD has been known to act as important regulator of tumor immunogenicity, specifically by influencing expression of the neoantigens. The tumor neoantigens are the targets for the immune system's attack because they are products of tumor-specific mutations resulting in peptides that are not present in healthy tissues, leading to a particularly specific T-cell response. A large percentage of such mutations; notably frameshift, nonsense or splice-site mutations frequently generate PTC-containing transcripts that are rapidly destroyed by NMD, thereby limiting generation of potentially immunologically significant neoantigenic peptides. Thus, targeting NMD has the potential to open new avenues for precision cancer therapy by revealing the previously unrealized immunogenic potential of tumors and bridging the gap between RNA biology and cancer immunotherapy. This review provides a comprehensive overview of various aspects of tumor neoantigens and also how NMD inhibition can be beneficial in the tumor immunotherapy process towards effective clinical implementation.