尽管可用的治疗方案取得了巨大进展并且黑色素瘤死亡率历史性下降，但转移性黑色素瘤仍是临床治疗中最神秘的晚期癌症之一。大多数接受现代靶向疗法（例如 BRAFV600E/K 抑制剂）和/或免疫检查点阻断（例如抗程序性死亡 1 疗法）治疗的转移性黑色素瘤患者都会出现进展，这是由于遗传和非遗传驱动的肿瘤细胞具有深刻的可塑性。机制和二分宿主微环境影响。在这里，我们讨论肿瘤异质性的决定因素、治疗耐药机制以及有希望治愈的有效治疗方案。© 2024。Springer Nature America, Inc.

Metastatic melanoma is among the most enigmatic advanced cancers to clinically manage despite immense progress in the way of available therapeutic options and historic decreases in the melanoma mortality rate. Most patients with metastatic melanoma treated with modern targeted therapies (for example, BRAFV600E/K inhibitors) and/or immune checkpoint blockade (for example, anti-programmed death 1 therapy) will progress, owing to profound tumor cell plasticity fueled by genetic and nongenetic mechanisms and dichotomous host microenvironmental influences. Here we discuss the determinants of tumor heterogeneity, mechanisms of therapy resistance and effective therapy regimens that hold curative promise.© 2024. Springer Nature America, Inc.