Metastatic melanoma (MM) is a pathological entity with a very poor prognosis that, until a few decades ago, had a low response rate to systemic treatments. Fortunately, in the last few years, new therapies for metastatic melanoma have emerged. Currently, targeted therapy and immunotherapy are the mainstays of the therapeutic arsenal available for patients with unresectable or metastatic melanoma. However, both clinical evolution and drug efficacy in melanoma patients are very different depending on the stage at which it is diagnosed. In fact, the aggressiveness of melanoma is different depending on whether it debuts directly as metastatic disease or if what occurs is a relapse after a first diagnosis at an early stage, although the biological determinants are largely unknown. Another key aspect in the clinical management of metastatic melanoma at first diagnosis strives in the different prognosis of melanoma of unknown primary (MUP) compared to melanoma of known primary (MPK). Understanding the mechanisms behind this, and the repercussion of implementing targeted and immune therapies in this specific form is crucial for designing diagnosis and treatment decision algorithms that optimize the current strategies. In this review article, we recapitulate the information available thus far regarding the epidemiology and response to immunotherapy treatments or targeted therapy in patients diagnosed with metastatic melanoma as a first diagnosis, with especial emphasis on the emerging specific information of the subpopulation formed by MUP patients.

Gut microbiome (GM) and its either pro-tumorigenic or anti-tumorigenic role is intriguing and constitutes an evolving landscape in translational oncology. It has been suggested that these microorganisms may be involved in carcinogenesis, cancer treatment response and resistance, as well as predisposition to adverse effects. In melanoma patients, one of the most immunogenic cancers, immune checkpoint inhibitors (ICI) and MAPK-targeted therapy—BRAF/MEK inhibitors—have revolutionized prognosis, and the study of the microbiome as a modulating factor is thus appealing. Although BRAF/MEK inhibitors constitute one of the main backbones of treatment in melanoma, little is known about their impact on GM and how this might correlate with immune re-induction. On the contrary, ICI and their relationship to GM has become an interesting field of research due to the already-known impact of immunotherapy in modulating the immune system. Immune reprogramming in the tumor microenvironment has been established as one of the main targets of microbiome, since it can induce immunosuppressive phenotypes, promote inflammatory responses or conduct anti-tumor responses. As a result, ongoing clinical trials are evaluating the role of fecal microbiota transplant (FMT), as well as the impact of using dietary supplements, antibiotics and probiotics in the prediction of response to therapy. In this review, we provide an overview of GM’s link to cancer, its relationship with the immune system and how this may impact response to treatments in melanoma patients. We also discuss insights about novel therapeutic approaches including FMT, changes in diet and use of probiotics, prebiotics and symbiotics. Finally, we hypothesize on the possible pathways through which GM may impact anti-tumor efficacy in melanoma patients treated with targeted therapy, an appealing subject of which little is known.