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In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance. Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA\u2010approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN\u2010\u03b12b, reduces melanoma proliferation, long\u2010term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM\u2010resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK\/AKT pathways by combined drug treatment. By using RNA\u2010sequencing and functional in vitro assays, we further report that romidepsin\u2010IFN\u2010\u03b12b treatment restores epigenetically silenced immune signals, modulates MITF and AXL expression and induces both apoptosis and necroptosis in sensitive and VEM\u2010resistant primary melanoma cells. Moreover, the immunogenic potential of drug\u2010treated VEM\u2010resistant melanoma cells results significantly enhanced, given the increased phagocytosis rate of these cells by dendritic cells, which in turn exhibit also a selective down\u2010modulation of the immune checkpoint TIM\u20103. Overall, our results provide evidence that combined epigenetic\u2010immune drugs can overcome VEM resistance of primary melanoma cells by oncogenic and immune pathways reprogramming, and pave the way for rapidly exploiting this combination to improve BRAFi\u2010resistant metastatic melanoma treatment, also via reinforcement of immune checkpoint inhibitor therapy.<\/jats:p>","DOI":"10.1002\/ijc.34602","type":"journal-article","created":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T10:07:41Z","timestamp":1686305261000},"page":"1080-1095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Reversing vemurafenib\u2010resistance in primary melanoma cells by combined romidepsin and type I <scp>IFN<\/scp> treatment through blocking of tumorigenic signals and induction of immunogenic 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