The uORF–NMD axis and uPeptides: a new frontier in cancer therapy

Nonsense-mediated decay (NMD) was first described as a surveillance mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it is now known that NMD also degrades a significant number of physiological transcripts, including some containing upstream open reading frames (uORFs). uORFs are mRNA cis -acting elements defined by a translation start codon in the 5′ transcript leader sequence in frame with a stop codon located upstream or overlapped with the main coding sequence (mCDS). Besides inducing NMD, translation of uORFs often represses translation of the mCDS, thereby maintaining mCDS-encoded proteins at low levels. However, translation of uORFs can also generate uORF-encoded peptides (uPeptides). These uPeptides may regulate critical cellular pathways. Recent technological advances in ribosome profiling and mass spectrometry techniques have allowed the detection of numerous uPeptides in both healthy and malignantly transformed human cells. Cancer cells can exhibit altered transcriptional landscapes, some of which are due to altered NMD activity, leading to the production of new uPeptides with roles in different cellular pathways; some of these can act as neoantigens. In this review, we aim to provide insight into the latest research on uPeptides and their functional roles in cellular pathways and during tumorigenesis. We also wish to explore the importance of NMD in regulating uPeptides’ expression in normal and cancer cells. Furthermore, we intend to review how these uPeptides contribute to expand the immunopeptidome, offering new targets for personalised cancer vaccines. Altogether, the collected data may help design new therapeutic approaches towards personalised medicine to fight cancer onset and development.