Secreted phospholipase A modifies extracellular vesicles and accelerates B cell lymphoma.

Extracellular vesicles (EVs) including exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of EV lipids remains unclear. Here, we show that the pro-tumorigenic action of lymphoma-derived EVs is augmented via secreted phospholipase A (sPLA)-driven lipid metabolism. Hydrolysis of EV phospholipids by group X sPLA, which was induced in macrophages of Epstein-Barr virus (EBV) lymphoma, increased the production of fatty acids, lysophospholipids, and their metabolites. sPLA-treated EVs were smaller and self-aggregated, showed better uptake, and increased cytokine expression and lipid mediator signaling in tumor-associated macrophages. Pharmacological inhibition of endogenous sPLA suppressed lymphoma growth in EBV-infected humanized mice, while treatment with sPLA-modified EVs reversed this phenotype. Furthermore, sPLA expression in human large B cell lymphomas inversely correlated with patient survival. Overall, the sPLA-mediated EV modification promotes tumor development, highlighting a non-canonical mechanistic action of EVs as an extracellular hydrolytic platform of sPLA.