Post-translational modifications in sEV biology: mechanisms and therapeutic applications in cancer

Small extracellular vesicles (sEVs) have garnered significant attention as key mediators of intercellular communication in cancer biology. Among sEV subtypes, exosomes represent a specialized population of strictly endosomal origin. Their biogenesis is a highly regulated, multi-step process. This process encompasses early endosome formation and cargo sorting. It is followed by the generation of intraluminal vesicles (ILVs). Multivesicular bodies (MVBs) then mature and are transported. They ultimately fuse with the plasma membrane to release exosomes. This entire pathway is governed by an integrated network of post-translational modifications (PTMs), including ubiquitination, phosphorylation, acetylation, and SUMOylation. These PTMs regulate key protein components involved in cargo sorting, MVB formation (ESCRT complexes, tetraspanins CD63/CD9/CD81), MVB transport (Rab GTPases), exosome secretion (ceramide pathway), and cellular uptake (integrins, heparan sulfate proteoglycans). In this review, we systematically dissect the molecular mechanisms by which distinct PTMs control sEV biology, with a particular focus on their contributions to cancer progression, immune modulation, and metastasis. We further discuss emerging therapeutic applications of sEVs in oncology, including their utility as drug delivery vehicles, immunotherapeutic agents, and diagnostic biomarkers. A comprehensive understanding of PTM-mediated sEV regulation will open new avenues for developing targeted therapeutic strategies and precision medicine approaches in cancer treatment.