Micropeptides in the oncological dark matter: decoding their roles in tumor progression and therapy resistance

Micropeptides are small peptide chains translated from non-coding RNAs (ncRNAs), typically ranging from < 100 to ~ 200 amino acids in length, and usually encoded by short or small open reading frames (sORFs/smORFs). Recent advances in high-throughput sequencing and multi-omics technologies have enabled genome-wide identification of sORFs across diverse species. Notably, a subset of these sORFs encodes functional micropeptides that play critical roles in biological processes such as inflammation, metabolism, and tumorigenesis. Emerging evidence suggests that tumor-associated micropeptides regulate key hallmarks of cancer, including proliferation, metastasis, metabolic reprogramming, angiogenesis, ion homeostasis, and immune evasion. In this review, we define the definition of micropeptides and discuss cutting-edge methodologies for their discovery, such as ribosome profiling (Ribo-seq), mass spectrometry (MS), and sORF-centric bioinformatics pipelines. Furthermore, we systematically summarize the functional mechanisms of micropeptides in tumor initiation, progression, therapeutic response, and drug resistance. This synthesis aims to provide novel perspectives on cancer biology and highlights micropeptides promising candidates for use as diagnostic biomarkers and targeted therapies.