Plasticity, signaling, and metabolic rewiring in melanoma persister cells

Abstract Despite advances in therapy, survival rates for metastatic melanoma remain low. Drug-tolerant persister cells (persisters) can facilitate cancer recurrence, yet their characteristics and vulnerabilities differ across cancers and even within melanoma, depending on mutational context and treatment strategy. Both preexisting phenotypic traits and drug-induced adaptations contribute to persister formation, linked by “primed” persisters that exhibit intermediate states observed in multiple studies. Compared with parental melanoma cells and other phenotypic variants such as melanoma stem cells or senescent cells, persisters show altered and reversible differentiation programs, distinct metabolic adaptations, and rewired signaling networks, all affected by the tumor microenvironment, but remain poorly understood. This review focuses on melanoma persisters, highlighting advances in understanding their origins, signaling plasticity, metabolic rewiring, and therapeutic vulnerabilities. By identifying gaps, this review further provides much-needed recommendations for future research and outlines priorities for advancing persister-directed interventions toward clinical translation.