Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior to the advent of targeted and immunotherapies, metastatic melanoma was considered a death sentence, with less than 5% of patients surviving more than 5 years. With the implementation of immunotherapies, approximately half of patients with metastatic melanoma now survive more than 5 years. Unfortunately, this also means that half of the patients with melanoma do not respond to current therapies and live less than 5 years after diagnosis. One major factor that contributes to lower response in this population is acquired or primary resistance to immunotherapies via tumor immune evasion. To improve the overall survival of melanoma patients new treatment strategies must be designed to minimize the risk of acquired resistance and overcome existing primary resistance. In recent years, many advances have been made in identifying and understanding the pathways that contribute to tumor immune evasion throughout the course of immunotherapy treatment. In addition, results from clinical trials focusing on treating patients with immunotherapy-resistant melanoma have reported some initial findings. In this review, we summarize important mechanisms that drive resistance to immunotherapies in patients with cutaneous melanoma. We have focused on tumor intrinsic characteristics of resistance, altered immune function, and systemic factors that contribute to immunotherapy resistance in melanoma. Exploring these pathways will hopefully yield novel strategies to prevent acquired resistance and overcome existing resistance to immunotherapy treatment in patients with cutaneous melanoma.