ISG15 and cancer: The secretion of IL6 and CXCL12 by CAF activates the JAK1/2-STAT3/5 pathway in cancer cells and enhances their proliferative and invasive abilities, while cancer cells themselves express a variety of downstream inflammation-related genes (e.g., IL6, TNF, IFI6, ISG15, etc.), forming self-excitation or positive feedback loops (75).