Novel insights into noncanonical open reading frames in cancer.

With technological advances, previously neglected noncanonical open reading frames (nORFs) are drawing ever-increasing attention. However, the translation potential of numerous putative nORFs remains elusive, and the functions of noncanonical peptides have not been systemically summarized. Moreover, the relationship between noncanonical peptides and their counterpart protein or RNA products remains elusive and the clinical implementation of noncanonical peptides has not been explored. In this review, we highlight how recent technological advances such as ribosome profiling, bioinformatics approaches and CRISPR/Cas9 facilitate the research of noncanonical peptides. We delineate the features of each nORF category and the evolutionary process underneath the nORFs. Most importantly, we summarize the diversified functions of noncanonical peptides in cancer based on their subcellular location, which reflect their extensive participation in key pathways and essential cellular activities in cancer cells. Meanwhile, the equilibrium between noncanonical peptides and their corresponding transcripts or counterpart products may be dysregulated under pathological states, which is essential for their roles in cancer. Lastly, we explore their underestimated potential in clinical application as diagnostic biomarkers and treatment targets against cancer.