PROTAC technology for sensitizing melanoma to immune checkpoint therapy

Abstract Melanoma remains one of the most aggressive malignancies, with limited response to immune checkpoint inhibitors (ICIs) due to primary or acquired resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality that induces selective degradation of target proteins via the ubiquitin–proteasome system, offering distinct advantages over conventional inhibitors. This review summarizes the design principles and molecular mechanisms of PROTACs, and highlights their emerging role in sensitizing melanoma to immunotherapy. Specifically, PROTACs can restore tumor antigen presentation, reprogram the immunosuppressive tumor microenvironment by targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and suppress key oncogenic signaling pathways. We also discuss combination strategies with PD-1/PD-L1 and CTLA-4 blockade, as well as current challenges including poor cell permeability, off-target effects, and acquired resistance. Finally, future perspectives on rational design, tissue-specific delivery systems, and clinical translation are addressed.