Fig. 1

Illustrative diagram for exosome-mediated transfer of therapeutic resistance in the tumor microenvironment (TME). Drug-resistant (donor) cells may communicate with drug-sensitive (recipient) cells by the intercellular transfer of various types of EVs, such as exosomes (usually expressing tetraspanins such as CD9/63/81, TSG101 and syntenin-1), which are of endocytic origin [124]. Upon fusion of secretory multivesicular bodies (MVBs) with the plasma membrane, exosomes are released into the extracellular space. The initial steps of this process are usually modulated by the endosomal sorting complex required for transport (ESCRT) [125]. The mechanisms involved in the release of exosomes are also regulated by other protein families, such as Rab GTPases and SNARES [125, 126]. Once EVs reach the recipient cells, they may fuse with their plasma membrane or be internalized by the endocytic pathway. Exosomes may transfer miRNAs, lncRNAs, proteins (such as drug-efflux pumps), and other key players responsible for drug resistance, which allows de novo development or horizontal dissemination of cancer resistance traits to the recipient cell populations. For example, mesenchymal stem cell (MSC)-derived exosomes trigger the activation of calcium-dependent protein kinases and EGFR/Ras/Raf/Mek/Erk kinase cascade in gastric cancer cells, while polarized macrophages promote cisplatin resistance of gastric cancer cells by exosomal transfer of miR-21 which functionally activates PI3K/AKT signaling via down-regulation of PTEN in recipient cells [127, 128]