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.
黑色素瘤是导致皮肤癌相关死亡的主要原因。免疫检查点抑制剂治疗通过显著提高患者生存率，彻底改变了该疾病的管理方式。然而，大量接受此类药物治疗的肿瘤未能产生应答，或可能随时间推移产生耐药性。肿瘤生长及其对治疗的反应受到肿瘤微环境的决定性影响：它直接支持癌细胞生长并影响周围免疫细胞的行为，这些免疫细胞可能转变为肿瘤许可状态，从而导致免疫疗法失效。建立黑色素瘤及其治疗反应的离体模型，将极大推动我们对治疗结果的理解与预测能力。目前研究重点在于开发能够精确模拟黑色素瘤在适宜组织环境中生长的可靠模型，包括肿瘤类器官、生物打印组织构建体和微流控装置。然而，如何整合并模拟黑色素瘤的肿瘤微环境及免疫组分仍是重大挑战。本文综述了近期关于正常皮肤与黑色素瘤体外三维模型构建的文献，以及在此类模型中整合免疫组分的方法。我们探讨了如何将这些构建体结合应用于免疫疗法测试及治疗耐药机制的解析。开发能够忠实复制肿瘤微环境复杂性及其与免疫系统相互作用的三维体外黑色素瘤模型，将为我们提供关键技术工具，以深入理解免疫检查点抑制剂耐药机制并提升其疗效，从而推动个性化黑色素瘤治疗的发展。
In Vitro Three-Dimensional (3D) Models for Melanoma Immunotherapy
肿瘤(癌症)患者之家