Exosomes secreted by ST3GAL5high cancer cells promote peritoneal dissemination by establishing a premetastatic microenvironment

Peritoneal dissemination of cancer affects patient survival. 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‐2,3‐sialyltransferase (ST3G5; also known as ST3GAL5 and GM3 synthase) in the exosome‐mediated premetastatic niche in peritoneal milky spots (MSs). Exosomes secreted from ST3G5high cancer cells (ST3G5high‐cExos) were found to contain high levels of hypoxia‐inducible factor 1‐alpha (HIF1α) and accumulated in MSs via uptake in macrophages (MΦs) owing to increased expression of sialic acid‐binding Ig‐like lectin 1 (CD169; also known as SIGLEC1). ST3G5high‐cExos induced pro‐inflammatory cytokines and glucose metabolic changes in MΦs, and the interaction of these MΦs with PMCs promoted mesothelial–mesenchymal transition (MMT) in PMCs, thereby generating αSMA+ myofibroblasts. ST3G5high‐cExos also increased the expression of immune checkpoint molecules and T‐cell exhaustion in MSs, which accelerated metastasis to the omentum. These events were prevented following ST3G5 depletion in cancer cells. Mechanistically, ST3G5high‐cExos upregulated chemokines, including CC‐chemokine ligand 5 (CCL5), in recipient MΦs and dendritic cells (DCs), which induced MMT and immunosuppression via activation of signal transducer and activator of transcription 3 (STAT3). Maraviroc, a C‐C chemokine receptor type 5 (CCR5) antagonist, prevented ST3G5high‐cExo‐mediated MMT, T‐cell suppression, and metastasis in MSs. Our results suggest ST3G5 as a suitable therapeutic target for preventing cExo‐mediated peritoneal dissemination.