Advanced cutaneous melanoma is the deadliest form of skin cancer and one of the most aggressive human cancers. Targeted therapies (TT) against BRAF mutated melanoma and immune checkpoints blockade therapies (ICB) have been a breakthrough in the treatment of metastatic melanoma. However, therapy-driven resistance remains a major hurdle in the clinical management of the metastatic disease. Besides shaping the tumor microenvironment, current treatments impact transition states to promote melanoma cell phenotypic plasticity and intratumor heterogeneity, which compromise treatment efficacy and clinical outcomes. In this context, mesenchymal-like dedifferentiated melanoma cells exhibit a remarkable ability to autonomously assemble their own extracellular matrix (ECM) and to biomechanically adapt in response to therapeutic insults, thereby fueling tumor relapse. Here, we review recent studies that highlight mechanical phenotypic plasticity of melanoma cells as a hallmark of adaptive and non-genetic resistance to treatment and emerging driver in cross-resistance to TT and ICB. We also discuss how targeting BRAF-mutant dedifferentiated cells and ECM-based mechanotransduction pathways may overcome melanoma cross-resistance.

晚期皮肤黑色素瘤是最致命的皮肤癌，也是最具侵袭性的人类癌症之一。针对BRAF突变黑色素瘤的靶向治疗（TT）和免疫检查点阻断疗法（ICB）已成为转移性黑色素瘤治疗的突破。然而，治疗驱动的耐药性仍然是转移性疾病临床管理的主要障碍。除了塑造肿瘤微环境外，目前的治疗还影响过渡状态以促进黑色素瘤细胞表型可塑性和肿瘤内异质性，这会损害治疗效果和临床结果。在这种情况下，间充质样去分化黑色素瘤细胞表现出非凡的能力，可以自主组装自己的细胞外基质 (ECM) 并在生物力学上适应治疗损伤，从而助长肿瘤复发。在这里，我们回顾了最近的研究，这些研究强调黑色素瘤细胞的机械表型可塑性是适应性和非遗传性治疗耐药性的标志，以及对 TT 和 ICB 交叉耐药性的新兴驱动因素。我们还讨论了靶向 BRAF 突变体去分化细胞和基于 ECM 的机械转导通路如何克服黑色素瘤交叉耐药性。