Described are methods for enhancing cancer immune surveillance and the efficacy of the treatment of melanoma or non-melanoma cancers such as pancreatic or colorectal cancers, particularly by controlling cancer cell-surface PD-L1/L2 and the E3 ligase ITCH. Also described are methods of inhibiting an adaptive immune resistance response to anti-immune checkpoint protein therapy in a subject. As described herein, the efficacy of MAPK inhibitor therapy is increased by treatment with an activator of E3 ligase ITCH or a destabilizer of cell-surface PD-L1/L2. As further demonstrated herein, the efficacy of anti-PD-1/L1 therapy is also increased by treatment with an activator of E3 ligase ITCH or a destabilizer of cell-surface PD-L1/L2.