Immune checkpoint inhibitors have revolutionized the treatment of advanced stage metastatic melanoma patients, as well as patients with many other solid cancers, yielding long lasting responses and improved survival. However, a subset of patients who initially respond to immunotherapy, later relapse and develop therapy resistance (termed acquired resistance), while others do not respond at all (termed primary resistance). Primary and acquired resistance are key clinical barriers to further improving outcomes of patients with metastatic melanoma and the known mechanisms underlying them involve various components of the cancer immune cycle, and interactions between multiple signalling molecules and pathways. Due to this complexity, current knowledge on resistance mechanisms is still incomplete. Overcoming therapy resistance requires a thorough understanding of the mechanisms underlying immune evasion by tumors. In this review, we explore the mechanisms of primary and acquired resistance to immunotherapy in melanoma, and detail potential therapeutic strategies to prevent and overcome them.
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