Remarkably, we found that different ISGs underlie resistance to ADU-S100 in different melanoma models, as B16 melanomas were most effectively treated with ADU-S100 + anti-PD-L1 or anti-ISG15 antibody, while BPR20 tumors were best treated with a combination of ADU-S100 + ARG2i/COX2i/NOS2i. Here, ISG15 is linked to melanoma.