نبذة مختصرة : Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma. ; I.A., P.A., D.E. and A.M. acknowledge funding from the Ministry of Economy and Competitiveness (Institute of Health Carlos III; refs. PI19/00645 to I.A., PI16-01911 to I.A., CPII20/00011 to I.A., CD21/00137 to P.A., PI20/00010 to D.E., PI20/00419 to D.E, PI19/01355 to A.M.). I.A. is also funded by Departamento de Salud del Gobierno de Navarra, Spain (ref. G°Na 71/17) D.A. acknowledges funding from The Spanish Association against Cancer (AECC; PROYE16001ESCO), Biomedicine Project Grant from the Department of Health of the Government of Navarre-FEDER funds (BMED 050-2019, 51-2021) and Strategic projects from the Department of Industry, Government of Navarre (AGATA, ref. 0011-1411; LINTERNA, ref. 0011–1411; DESCARTHES, 0011-1411-2019-000058). M.R.-M. is funded ...
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