Several studies have revealed enhanced expression of ISG15 and deregulation of enzymes that catalyze ISGylation and de-ISGylation in many types of cancers, involving bladder cancer, breast cancer, prostate cancer, hepatocellular carcinoma, colorectal cancer, nasopharyngeal carcinoma, gastric cancer, oesophageal squamous cell carcinoma [42], and OSCC [43,44]. Here, ISG15 is linked to hepatocellular carcinoma.