Abstract
Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved survival outcomes and radically changed the management of many different types of solid tumors, including melanoma. Almost half of advanced melanoma patients achieve a long-term clinical benefit from ICIs. Unfortunately, the other half of treated patients either rapidly progress or achieve a short-term clinical benefit due to the development of resistance. As a result, novel therapeutic strategies are urgently needed to overcome ICI resistance. Epigenetic alterations affecting the tumor neoantigen presentation system or modifying the tumor microenvironment can mitigate ICI resistance. Several studies have demonstrated that epigenetic alterations are potentially targetable by epigenetic modifiers, laying the foundation for the development of novel therapeutic strategies to overcome ICI resistance. In the present work, we summarize the major epigenetic alterations involved in the pathogenesis of melanoma and their role in ICI resistance. Preclinical evidence supporting the biological rationale for combining epigenetic modifiers with ICIs and an updated overview of the main clinical trials testing epigenetic modifiers for the treatment of melanoma patients will be presented.