Background/Objectives: This review discusses the resistance mechanisms in the tumor microenvironment (TME) of malignant melanoma that disrupt the efficacy of immune checkpoint inhibitors (ICIs). In this review, we focus on the roles of immune cells, including tumor-infiltrating lymphocytes (TILs), macrophages, dendritic cells, and other signaling pathways. We explore the interplay between innate and adaptive immunity in the TME and tumor intrinsic resistance mechanisms, such as β-catenin, which has future implications for the usage of ICIs in patients with therapy-resistant tumors. Methods: A total of 1052 studies were extracted from the PubMed database searching for keywords and phrases that included [melanoma AND immune checkpoint inhibitor resistance]. After a title/abstract and full-text review, 101 studies were identified that fit the inclusion/exclusion criteria. Results: Cancer-associated fibroblasts (CAFs), M2 macrophages, and myeloid-derived suppressor cells (MDSCs) are significant in remodeling the TME to promote melanoma growth. Melanoma resistance to ICIs is complex and involves TME alterations, tumor intrinsic factors, and immune evasion. Key components of resistance include reduced CD8+ T cell infiltration, decreased host immune response, and immunosuppressive cytokines. Conclusions: Predictive biomarkers and specific models are the future of individualized melanoma management and show great promise in their approach to targeted therapy production. Tumor profiling can be utilized to help predict the efficacy of ICIs, and specific biomarkers predicting therapy responses are instrumental in moving towards personalized and more efficacious medicine. As more melanoma resistance emerges, alternative and combinatorial therapy based on knowledge of existing resistance mechanisms will be needed.

The immune repertoire (IR) is a term that defines the combined unique genetic rearrangements of antigen receptors expressed by B and T lymphocytes. The IR determines the ability of the immune system to identify and respond to foreign antigens while preserving tolerance to host antigens. When immune tolerance is disrupted, development of autoimmune diseases can occur due to the attack of self-antigens. Recent technical advances in immune profiling allowed identification of common patterns and shared antigen-binding sequences unique to diverse array of diseases. However, there is no current literature to date evaluates IR findings in autoimmune and skin inflammatory conditions. In this review, we provide an overview of the past and current research findings of IR in various autoimmune and dermatologic conditions. Enriching our understanding of IRs in these conditions is critical for understanding the pathophysiology behind autoimmune skin disease onset and progression. Furthermore, understanding B-cell and T-cell IR will help devise therapeutic treatments in the hopes of restoring immune tolerance and preventing disease onset and progression.