Melanoma Immunotherapy and Precision Medicine in the Era of Tumor Micro-Tissue Engineering: Where Are We Now and Where Are We Going?

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. ABSTRACT: 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.