Evolving cancer resistance to anti-PD-1/PD-L1 antibodies in melanoma: Comprehensive insights with future prospects
W. Li, Junjie Gu, Hongwei Fan, Li Zhang, Jun Guo, Lu Si
Abstract
Immunotherapy has transformed the treatment of advanced melanoma. However, up to two-thirds of patients experience disease progression after initially achieving a response to immunotherapy. Furthermore, most research has focused on cutaneous melanoma rather than acral or mucosal melanoma, although the latter predominates in Asian populations. In this review, we examine and summarize current definitions of resistance to immunotherapy and the epidemiology of resistance to PD-1 inhibition. We also review the available literature on molecular mechanisms of resistance, including how the tumor mutational landscape and tumor microenvironments of immunotherapy-resistant acral and mucosal melanomas may influence resistance. Finally, we review strategies for overcoming resistance to PD-1 inhibition and summarize completed studies and ongoing clinical trials. Our review highlights that improving the understanding of resistance mechanisms, optimizing existing therapies and further studying high-risk populations would maximize the potential of immunotherapy and result in optimized treatment outcomes for patients with melanoma. • The incidence of melanoma is increasing worldwide by up to 5 % each year. • Immunotherapy, including PD-1 inhibitors, has revolutionized melanoma treatment. • However, a notable proportion of patients develop resistance to PD-1 inhibition. • We review current evidence and propose strategies to overcome anti-PD-1 resistance.