ISG15 and neoplasm: ISG15, like ubiquitin, can either be present in its free form, which can be secreted to the TME to influence tumor adjacent cells (52), or be covalently conjugated to the lysine (K) residues of target proteins using specific E1 (UBE1L), E2 (UBCH8), and E3 (TRIM family members, etc.)enzymes by a process termed ISGylation (53).