Unfortunately, the phase III results of the epacadostat (IDO inhibitor) plus pembrolizumab (anti-PD1/PD-L1 monoclonal antibody) combination in metastatic melanoma were disappointing, highlighting the fact that this type of interventional target is not easily modulated; they represent a major challenge requiring finely tuned approaches, preferably based on reliable biomarkers and new technical strategies selectively targeting TME. The gene discussed is IDO1; the disease is metastatic melanoma.