Using quantitative proteomics, pathway and network analyses, EV database resources, and bioinformatics analyses, we report a mesothelioma-enriched exosome protein cancer signature (mEXOS), associated with tumour antigens and various cancer-specific signalling (HPGD, ENO1, EDIL3, OSMR) and secreted modulators (FN1, ITLN1, MAMDC2, PDGFD, GBP1). Here, HPGD is linked to mesothelioma.