Abstract
Phenotypic plasticity and drug tolerance are now recognized as major causes of tumor aggressiveness and therapy resistance. Melanoma represents a paradigmatic example of how solid tumors exploit non-genetic adaptive programs, including the transition between proliferative and dormant states and the emergence of drug-tolerant persister cells, that sustain intratumoral heterogeneity and survive targeted and immune-based therapies. Increasing evidence shows that miRNAs are critical elements controlling these processes both directly, via shaping gene expression programs that enable cell plasticity, and indirectly, through vesicle-mediated communication that spreads resistant traits and remodels the tumor microenvironment. The combined impact on cell-intrinsic and cell-extrinsic pathways position miRNAs as promising biomarkers and therapeutic targets across malignancies. Even though early therapeutic efforts faced challenges in delivery and stability, recent advances in chemically modified antisense oligonucleotides, particularly locked nucleic acids (LNAs), have renewed interest in targeting oncogenic miRNAs in metastatic disease. This review combines current knowledge on phenotypic plasticity, drug-tolerant states and microenvironmental remodeling, with miRNA regulation, highlighting how insights gained from melanoma can shape the development of clinically relevant LNA-based therapeutics.