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Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10-15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and immunotherapeutic strategies has improved chances for patient survival, melanoma treatment still remains a big challenge for oncologists. Here, we collect recent data about the emerging role of melanoma-associated microRNAs (miRNAs) currently available treatments, and their involvement in drug resistance. We also reviewed miRNAs as prognostic factors, because of their chemical stability and resistance to RNase activity, in melanoma progression. Moreover, despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors., Competing Interests: The authors declare no conflict of interest.

Simple Summary: Melanoma is a cancer with very poor survival rates, although its treatment has been revolutionized by targeted therapy and immunotherapy. It is a complex disease, where dynamic interactions, not only among melanoma cells themselves, but also between tumor cells and their surroundings, occur. This review focuses on melanoma complexity, pointing out how melanoma cells are only a part of a large ecosystem and the tumor microenvironment plays an active role on their evolution and ability to escape to drug treatment. The recent efforts addressed to the development of ex-vivo micro-tissue models able to recapitulate the live conditions of melanoma cells in human patients have been outlined. Further, the use of ex-vivo models as a novel approach for the researcher to investigate the mechanisms underlying tumor biology and immunotherapeutic resistance in metastatic melanoma has been discussed, as well as their high potential for the development of personalized medicine in melanoma treatment. Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response to therapies can be shaped by not only taking into account cancer cell heterogeneity and plasticity, but also by its structural context as well as the cellular component of the tumor microenvironment (TME). Here, we review the recent development in the field of immunotherapy and target-based therapy and how, in the era of tumor micro-tissue engineering, ex-vivo assays could help to enhance our melanoma biology knowledge in its complexity, translating it in the development of successful therapeutic strategies, as well as in the prediction of therapeutic benefits. [ABSTRACT FROM AUTHOR]