Micropeptides in Cancer and Immunity: Diagnostic, Therapeutic, and Synthetic Biology Frontiers

Micropeptides are emerging as a previously hidden layer of the human proteome, redefining the long-standing separation between coding and noncoding genomic regions. Once dismissed as translational noise, sORFs embedded within lncRNAs, circRNAs, pseudogenes, and UTRs are now recognized as a reservoir of functional peptides that regulate core cellular programs, including metabolism, mitochondrial function, immune signaling, and stress adaptation. In cancer, micropeptides exert dual and context-dependent roles: oncogenic micropeptides such as SMIM30, circPDHK1-241aa, and PDL1P41 promote proliferation, angiogenesis, immune escape, and therapeutic resistance, whereas tumor-suppressive peptides, including HOXB-AS3, CIP2A-BP, SPAR, and ASRPS, restore metabolic homeostasis, reactivate the PP2A axis, inhibit mTORC1, and block tumor vascularization. Their small size, modular structure, and tissue specificity make them ideal biomarkers for liquid biopsies and attractive substrates for peptide-based and mRNA-encoded therapeutics. Emerging frameworks integrating single-cell proteogenomics, Ribo-seq, mass spectrometry, and deep-learning-based structural inference are accelerating micropeptide discovery and annotation. Synthetic biology now enables the rational design of micropeptide-based therapeutic constructs, including tumor-specific mRNA-encoded peptides, CRISPR-activated peptide circuits, and targeted peptide chimeras. Collectively, micropeptides represent a transformative paradigm, bridging genomics and proteomics, and establishing the hidden proteome as a new frontier in precision oncology, immunotherapy development, and programmable cancer therapeutics.