MAPK Inhibitor‐Tolerant Persister Cells in Melanoma: Mechanisms and Therapeutic Vulnerabilities

Though major advancements have been made within the realm of targeted and immune-based therapies, metastatic melanoma still remains one of the most notoriously incurable malignancies due to early drug tolerance and eventual resistance. Increasing evidence has started to show drug-tolerant persister cells as a critical nongenetic mechanism that allows survival under MAPK pathway inhibition. While genetically resistant clones support stable mutations, persister cells enter reversible, slow-cycling states which are triggered by stressful conditions. This review synthesizes current research on the various molecular and cellular mechanisms which support melanoma persister cell formation, focusing specifically on phenotype plasticity, selective translational control, metabolic rewiring, redox buffering, and compensatory signaling pathways. We highlight how dynamic transitions among MITF-low, SOX10-low, and KDM5B-high states enable persistence under therapeutic pressure, and how epitranscriptomic regulation and metabolic shifts toward oxidative/lipid-dependent processes help decouple and focus on survival rather than proliferation. Furthermore, we examine microenvironment-driven activation of RhoA-FAK-AKT signaling and redox-adaptive sulfur metabolism as unique adaptive resistance mechanisms. Finally, our paper emphasizes persister states serving as evolutionary intermediates from which stable resistance can eventually emerge, and outline therapeutic strategies which exploit the transient persister vulnerability and help prevent melanoma drug-resistance.