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The behavior of peritoneal mesothelial cells (PMCs) and immune cells influences the establishment of a microenvironment that promotes cancer cell metastasis in the peritoneum. Here, we investigated the roles of lactosylceramide alpha\u20102,3\u2010sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome\u2010mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from <jats:italic>ST3G5<\/jats:italic><jats:sup>high<\/jats:sup> cancer cells (ST3G5<jats:sup>high<\/jats:sup>\u2010cExos) were found to contain high levels of hypoxia\u2010inducible factor 1\u2010alpha (HIF1\u03b1) and accumulated in MSs via uptake in macrophages (M\u03a6s) owing to increased expression of sialic acid\u2010binding Ig\u2010like lectin 1 (<jats:italic>CD169<\/jats:italic>; also known as <jats:italic>SIGLEC1<\/jats:italic>). ST3G5<jats:sup>high<\/jats:sup>\u2010cExos induced pro\u2010inflammatory cytokines and glucose metabolic changes in M\u03a6s, and the interaction of these M\u03a6s with PMCs promoted mesothelial\u2013mesenchymal transition (MMT) in PMCs, thereby generating \u03b1SMA<jats:sup>+<\/jats:sup> myofibroblasts. ST3G5<jats:sup>high<\/jats:sup>\u2010cExos also increased the expression of immune checkpoint molecules and T\u2010cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following <jats:italic>ST3G5<\/jats:italic> depletion in cancer cells. Mechanistically, ST3G5<jats:sup>high<\/jats:sup>\u2010cExos upregulated chemokines, including CC\u2010chemokine ligand 5 (CCL5), in recipient M\u03a6s and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C\u2010C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5<jats:sup>high<\/jats:sup>\u2010cExo\u2010mediated MMT, T\u2010cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo\u2010mediated peritoneal dissemination.<\/jats:p>","DOI":"10.1002\/1878-0261.13524","type":"journal-article","created":{"date-parts":[[2023,9,17]],"date-time":"2023-09-17T02:45:00Z","timestamp":1694918700000},"page":"21-43","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Exosomes secreted by <scp><i>ST3GAL5<\/i><sup>high<\/sup><\/scp> cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment"],"prefix":"10.1002","volume":"18","author":[{"given":"Misato","family":"Horie","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Biochemistry Akita University Graduate School of Medicine  Japan"},{"name":"Department of Gastroenterological Surgery Akita University Graduate School of Medicine  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