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The development of unprecedent melanoma quadruple multicellular tumoroids (MCTs) is proposed comprising tumor cells, keratinocytes, fibroblasts, and monocytes that replicate tumor architecture, tumor microenvironment, and secretome behavior. These MCTs of 300\u00a0\u00b5m in diameter secreted keratin and collagen, showing complexity proportional to their cell combinations. Further, closely resembled in vivo tumors in terms of cells organization, growth, progression, and immune behavior. Drug screening using these MCTs demonstrated their potential as patient\u2010derived platforms for precision medicine. 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