In mouse melanoma models it was demonstrated that by coating the viral envelope with peptides, the number of tumor-specific CD8+ T cells was enhanced (103). outline of immune cells can offer innovative insights in new therapy targets and cancer therapeutical approaches. In addition to already approved immune- and targeted therapy in melanoma, approaching metabolic check-points could improve therapy efficacy and hinder resistance to therapy. heterogeneous starting from its genetic traits and ending with the variable microenvironment conditions where the tumor is developing. A series of drugs that target metabolism pathways has shown clear clinical benefits in trials (11). For example, L-asparaginase targeting aminoacid metabolism was already approved in acute lymphocytic leukemia; metformin alone or in combination for stage III-IV head and neck squamous cell cancer is in the clinical evaluation trials (12). Intense preclinical studies performed on cell lines, primary tumor cells and models have shown that metabolic enzymes can be depicted as cancer therapy targets. Current concentrated studies efforts gather to understand tumor cell metabolism and all the factors that are conjoining to tumor’s overall biological behavior. There is a common flow of events in tumorigenesis, and the most commonly accepted stages are the genetic events that activate signaling pathways for Cysteamine HCl various deregulated cellular functions, including metabolic pathways. The fact that at molecular level deregulated cell’s functions in tumorigenesis are linked with deregulated metabolic functions has open new therapeutic doors in cancer (13). Another important point to be taken into account when investigating tumor cell metabolism is the fact that cancerous cells are in Cysteamine HCl intimate contact with non-tumor cells, with various microenvironment structures and molecules (14) that will lead to the overall metabolic out-line of a tumor. Out of all non-tumor cells, immune cells that infiltrate the tumor are one of the most important cellular populations. In solid tumors, including melanoma and non-melanoma tumors, the tumor microenvironment (TME) is in the 5.7C7.0 pH range, therefore within the tumors, immune cells that infiltrate them will be subjected to this acidosis. Actually, innate and adaptive immune cells are regulated by acidic pH that is found generally in inflammation. Therefore, when immune cells infiltrate the tumor, they will be subjected to this acidicinflammatory milieu. When immune cells are subjected to this acidicinflammatory milieu they will trigger a series of events. Neutrophils will trigger anti-apoptosis events and differentiation process toward pro-angiogenic cellular patterns. Monocytes and macrophages will have their inflammasome activated inducing IL-1 synthesis. Conventional dendritic cells (cDC) will turn into a mature phenotype. All these cellular profiles indicate that innate immune cells recognize low pH as a danger-associated molecular pattern (DAMP). Adaptive immune cells will be as well-altered by low pH. T lymphocytes, with cytotoxic function will be repressed by low pH and IFN- production performed by T helper 1 (Th1) cells will be hindered. The mere raise in pH in the tumor microenvironment can reverse T lymphocyte anergy and enhance the antitumor immune response triggered by checkpoint inhibitors (15). Therefore, in the attempt to review the metabolic profile of cutaneous melanoma, besides the actual metabolic profile of the tumor cell and models (27). Guanosine monophosphate reductase is involved in purine biosynthesis and if the expression of guanosine monophosphate reductase is reduced, Cysteamine HCl melanoma aggressiveness is enhanced. Decreasing intracellular GTP pools can limit melanoma cell’s invasiveness as it was confirmed in invasive melanomas that guanosine monophosphate reductase is down-regulated (28). Although new immune therapies have been approved for cutaneous melanoma (29, 30) the lack / poor clinical responses sustain the necessity to add new targets, such as altered metabolic enzymes / pathways that can aid or even can personalize therapy in melanoma. In melanoma cells, as stated above, cytosolic serine pathway is upregulated. Inhibition of this metabolic pathway in other cancers (31) can be also extended to melanoma. Thus, if inhibiting serine biosynthetic pathway, oxidative stress can be induced in tumor cells. Higher ROS (reactive oxygen species) generation, reduces invasiveness because RHOA/GTP activity is decreased. Hypoxia drives glutamine pathways for fatty acid biosynthesis. Down-regulation of glycolysis upregulates oxidative phosphorylation to reinstate ATP levels needed for proliferation. Therefore, if BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors can be combined with mitochondrial function inhibitors melanoma cell proliferation can be blocked at both levels. For example, introducing biguanides Rabbit Polyclonal to mGluR7 (metformin or phenformin) or glutaminase inhibitor BPTES the resistance to BRAF inhibitors will.