Strategies to rewire the metabolic asset of the TME. Schematic illustration of the different metabolic alteration in the TME and the available options to rewire its physiological status. Upon relapse after allo-HCT, AML cells (in violet) can impair donor T-cell (in red) proliferative potential and cytotoxic functions through LA release. Metabolic reprogramming through the administration of Bicanorm (NaBi), which antagonizes LA-induced effects, represent an optimal strategy to restore T-cell fitness and functions. In addition, azithromycin administration is directly involved in T-cell global impairment because it specifically inhibits T-cell effector functions and alters the gut microbiome with defects being associated with specific plasma metabolite signatures and with the accumulation of exhausted T cells. To counteract these effects, administration of probiotics and fecal microbiota transplantation can be useful approaches to restore the composition of the microbiome. The conditioning regimen and GVHD can alter the plasmatic oxidative balance, which can lead to an accumulation of ROS that, in turn, hampers T-cell functions. Administration of antioxidants can be a rational therapeutic approach to decrease ROS levels and reinstate redox balance.