Environmental cues within the tumor microenvironment (TME) affect tumor heterogeneity and plasticity, ultimately influencing therapy responses. Recent studies have shown that cancer stem cell niches are located near blood vessels and thus may be exposed to abrupt changes in the osmotic conditions. Here, we investigated how osmotic stress induced by the TME contributes to the generation of drug-tolerant persister cells in melanoma. Our research provide evidence that osmotic stress promotes cancer cell adaptation and reprogramming toward an NCSC-like state, with long non-coding RNAs (lncRNAs) emerging as likely (and druggable) mediators of this mechanical stress, converting osmotic gradients into specific molecular signals. Critically, we have identified MOMO (Melanoma Osmosis MediatOr) as a novel transcript deregulated upon osmotic stress and associated with poor prognosis in melanoma. Our findings suggest that MOMO plays a crucial role in osmotic stress-induced adaptive reprogramming in melanoma by acting as a key player in the DNA Damage Response, thereby altering tumor composition and impacting therapy outcomes.