ISG15 and central nervous system cancer: In ovarian cancer, free ISG15 can inhibit the phenotypes of cancer stem cells (CSCs) to attenuate cisplatin resistance [37]; in liver cancer and cervical cancer, free ISG15 can promote the upregulation of p53/p21 expression, thereby inhibiting tumor progression [38,39]; and in glioma, free ISG15 could improve the stability of OCT4 to enhance the stemness of cells [40] (Figure 2B).