In response to type I IFNs produced by PDAC cells, ISG15 is secreted from tumor-associated macrophages (TAMs) and aggravates the tumorigenicity of CSCs by reinforcing CSC self-renewal, invasive capacity, and tumorigenic potential, which suggests key roles of ISG15 in the pathogenesis and progression of CSCs in the PDAC microenvironment210. The gene discussed is ISG15; the disease is neoplasm.