Intrahepatic cholangiocarcinoma (ICC) is a type of cancer that is difficult to cure; chemoresistance of cholangiocarcinoma cells affect the prognosis of patients who cannot be treated with surgery. The mechanism underlying this chemoresistance remains unknown. Mesenchymal stem cells (MSCs) are known to be important components of the tumor microenvironment. In the present study, a large number of MSCs were observed to infiltrate the tumor sites of ICC; thus, MSCs were isolated from ICC tumor tissues. It was revealed that herpesvirus entry mediator (HVEM) was overexpressed in ICC-MSCs. The present study then investigated the role of HVEM-overexpressing MSCs in the chemoresistance of cholangiocarcinoma cells. It was demonstrated that HVEM-overexpressing MSCs could support cell survival of chemotherapeutic cholangiocarcinoma cells and inhibited their apoptosis. Further investigations revealed that HVEM-overexpressing MSCs could secrete IL-6 and also activated AMPK/mTOR-dependent autophagy of cholangiocarcinoma cells. Thus, it was concluded that ICC-MSC-induced autophagy is the primary cause of chemoresistance in ICC.

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