Schimmer et al. proved that inhibiting the E1-activating enzyme UBA1 reduced leukemia burden and specifically targeted leukemia stem cells [20]; Ma et al. demonstrated that the E2-conjugating enzyme UBE2B promoted ovarian cancer growth [21]; Wang et al. discovered that deleting the E3 ligases TRIM29 inhibited PDAC’s cancer stem cell-like properties by accelerating ISG15 degradation [22]; Lee et al. revealed that USP1-mediated protein stabilisation promoted GSC maintenance and treatment resistance [23]. Here, ISG15 is linked to cancer.