The hidden players: LncRNA-Encoded micropeptides in cancer hallmarks.

Traditionally, long non-coding RNAs (lncRNAs) were considered non-protein-coding. However, recent studies reveal that their short open reading frames (sORFs) can translate functional micropeptides (10–100 amino acids), forming “bifunctional RNAs” with dual RNA and polypeptide functions. This review summarizes the mechanistic roles and clinical significance of lncRNA-encoded micropeptides in tumor development. By integrating ribosome footprinting sequencing (Ribo-seq), mass spectrometry, and bioinformatic prediction, researchers have identified numerous tumor-associated micropeptides (e.g., APPLE, RBRP, CIP2A-BP). These micropeptides drive malignant progression by regulating key oncogenic processes, including sustained proliferative signaling (e.g., enhancing translation initiation complex assembly), evasion of growth suppression (e.g., blocking tumor-suppressive pathways), and metabolic reprogramming (e.g., activating ATP synthase). Notably, micropeptide functions align with Hanahan & Weinberg’s hallmarks of cancer framework, highlighting their centrality in tumor biology. The expression levels of specific micropeptides (e.g., MIAC, SMIM30) correlate significantly with patient prognosis, demonstrating their potential as novel diagnostic biomarkers and therapeutic targets. Although challenges in stability and delivery exist for micropeptide-based drugs, their high specificity and low toxicity offer promising avenues for precision cancer therapy.