Several evidences indicate that melanoma, one of the deadliest types of cancer, presents the ability to transiently shift its phenotype under treatment or microenvironmental pressure to an invasive and treatment-resistant phenotype, which is characterized by cells with slow division cycle (also called slow-cycling cells) and high-OXPHOS metabolism. Many cellular marks have been proposed to track this phenotype, such as the expression levels of the master regulator of melanocyte differentiation (MITF) and the epigenetic factor JARID1B. It seems that the slow-cycling phenotype does not necessarily present a single gene expression signature. However, many lines of evidence lead to a common metabolic rewiring process in resistant cells that activates mitochondrial metabolism and changes the mitochondrial network morphology. Here, we propose that mitochondria-targeted drugs could increase not only the efficiency of target therapy, bypassing the dynamics between fast-cycling and slow-cycling, but also the sensitivity to immunotherapy by modulation of the melanoma microenvironment.

一些证据表明，黑色素瘤是最致命的癌症类型之一，具有将其在治疗或微环境压力下的表型瞬时转变为侵袭性和对治疗有抵抗力的表型的能力，其特征在于细胞分裂周期缓慢（也称为慢速循环细胞）和高OXPHOS代谢。已经提出了许多细胞标记来追踪这种表型，例如黑素细胞分化的主调节因子（MITF）的表达水平和表观遗传因子JARID1B。似乎慢循环表型不一定呈现单个基因表达特征。然而，许多证据导致耐药细胞中常见的代谢重排过程，该过程激活了线粒体代谢并改变了线粒体网络形态。在这里，我们建议针对线粒体的药物不仅可以提高靶向治疗的效率，绕开快速循环和慢速循环之间的动态关系，还可以通过调节黑素瘤微环境来提高免疫治疗的敏感性。