In Vitro Three-Dimensional (3D) Models for Melanoma Immunotherapy

Simple Summary Melanoma treatment has progressed through the use of immune checkpoint inhibitors, significantly boosting patient survival rates. However, many tumors do not respond to these drugs or develop resistance, partly due to the tumor microenvironment influencing cancer cell growth and immune cell behavior. To gain insights into therapy outcomes, researchers have focused on developing cell-based ex vivo models of melanomas. These models include tumor organoids, engineered tissues, and microfluidic devices designed to replicate melanoma in its natural skin environment. Yet, integrating the tumor microenvironment and immune factors remains challenging. This review explores the creation of in vitro 3D models for normal skin and melanoma, focusing on methods to include immune components. These models hold promise for testing immunotherapies and uncovering resistance mechanisms. By faithfully replicating the tumor microenvironment and its interactions with the immune system, these models can enhance our understanding of immunotherapy resistance and ultimately improve personalized melanoma treatment.Abstract Melanoma is responsible for the majority of skin cancer-related fatalities. Immune checkpoint inhibitor (ICI) treatments have revolutionized the management of the disease by significantly increasing patient survival rates. However, a considerable number of tumors treated with these drugs fail to respond or may develop resistance over time. Tumor growth and its response to therapies are critically influenced by the tumor microenvironment (TME); it directly supports cancer cell growth and influences the behavior of surrounding immune cells, which can become tumor-permissive, thereby rendering immunotherapies ineffective. Ex vivo modeling of melanomas and their response to treatment could significantly advance our understanding and predictions of therapy outcomes. Efforts have been directed toward developing reliable models that accurately mimic melanoma in its appropriate tissue environment, including tumor organoids, bioprinted tissue constructs, and microfluidic devices. However, incorporating and modeling the melanoma TME and immune component remains a significant challenge. Here, we review recent literature regarding the generation of in vitro 3D models of normal skin and melanoma and the approaches used to incorporate the immune compartment in such models. We discuss how these constructs could be combined and used to test immunotherapies and elucidate treatment resistance mechanisms. The development of 3D in vitro melanoma models that faithfully replicate the complexity of the TME and its interaction with the immune system will provide us with the technical tools to better understand ICI resistance and increase its efficacy, thereby improving personalized melanoma therapy.