癌症的腹腔播散影响患者的生存。腹膜间皮细胞（PMCs）和免疫细胞的行为影响了在腹膜中促进癌细胞转移的微环境的形成。在这里，我们研究了乳糖基鞘脂丙型2，3-唾液酸转移酶（ST3G5；也称为ST3GAL5和GM3合成酶）在腹膜乳白色斑点（MSs）中通过外泌体介导的前转移损害中的作用。由ST3G5高表达的癌细胞（ST3G5high-cExos）分泌的外泌体含有高水平的缺氧诱导因子1-alpha（HIF1α），并通过巨噬细胞（MΦs）摄取积累在MSs中，这是由于乳酸酸结合免疫球蛋白样凝集素1（CD169；也称为SIGLEC1）的表达增加。 ST3G5高表达的cExos在MΦs中诱导促炎细胞因子和葡萄糖代谢变化，并且这些MΦs与PMCs的相互作用促进PMCs的间皮-间质转变（MMT），从而产生αSMA+肌成纤维细胞。 ST3G5高表达的cExos还增加了MSs中免疫检查点分子和T细胞耗竭的表达，从而加速转移到网膜。在癌细胞中ST3G5耗材后，这些事件得到了防止。机制上，ST3G5高表达的cExos在受体MΦs和树突状细胞（DCs）中上调了多种趋化因子，包括CC-趋化因子配体5（CCL5），从而通过激活信号转导子和活化因子3（STAT3）诱导MMT和免疫抑制。C-C趋化因子受体5（CCR5）拮抗剂Maraviroc可防止ST3G5高表达的cExo介导的MMT，T细胞抑制和MSs转移。我们的研究结果表明，ST3G5是预防cExo介导的腹膜播散的适宜治疗靶点。本文受版权保护，版权所有。

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 pre-metastatic 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.This article is protected by copyright. All rights reserved.