ISG15 and pancreatic ductal adenocarcinoma: Of note, in pancreatic ductal adenocarcinoma (PDAC), not only does ISG15 extracellular paracrine-signalling play a key role in CSC maintenance [27, 28], but also the intracellular ISG15 and ISGylation are required for CSC metabolic plasticity and mitophagy [29].