The application of immune-based therapies has revolutionized cancer treatment.,Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood.,In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair.,Whether MITF also controls the immune response is unknown.,By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response.,ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene.,Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing.,Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells.,By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system.,Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance.,Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.,The online version contains supplementary material available at 10.1186/s13046-021-01916-8.
Despite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance.,While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug.,Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment.,Cells that escape drug rely on ATF4 stress signalling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment.,Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.,BRAF inhibitors are used to treat late-stage melanoma patients harbouring BRAF mutations.,Here the authors track the responses of single melanoma cells to BRAF inhibitors and show that a subset of cells rapidly escapes drug via non-genetic mechanisms and incurs DNA damage.