Abstract: 【Abstract】 Melanoma is a highly malignant immunogenic tumor. Although immunotherapy represented by immune checkpoint inhibitors can markedly improve the survival rate of patients with metastatic melanoma, nearly half of patients are still tolerant or resistant to immunotherapy, with high incidence of immune-related adverse reactions. This review focuses on the key difficulties in tolerance, resistance and immune-related adverse reactions to current melanoma immunotherapy, and summarizes corresponding strategies and research advances. By intervening in the immunosuppressive microenvironment in melanoma, screening precise biomarkers, and optimizing immunotherapy-based combination strategies, the problem of tolerance and resistance to immunotherapy can be solved. Moreover, the combination of traditional immunotherapy and nanotechnology can also greatly reduce the occurrence of immune-related adverse reactions. In the future, more extensive and in-depth research on the tumor immune microenvironment will help to explore the best immunotherapy regimens for melanoma.

Key words: Nevi and melanomas, Immunotherapy, Biological agents, Immune tolerance, Immune-related adverse effects, Biomarkers