Metabolic alterations in the TME: consequences on tumor cells and immune cells. The energy supply needed by tumor cells to secure their survival and expansion in the TME is met by the enhanced utilization of nutrients locally available (i.e., glucose and amino acids). Far from being ecologically sustainable, the metabolic changes operated by tumor cells in the TME lead to the release of toxic waste that are responsible for the induction of a progressively hypoxic, acidic, and poor in nutrients TME. The immune cells respond in a different way to these challenges: toxic metabolites (i.e., lactate, kinurenines, Ado, etc) promote the activation of suppressor cells like Tregs, MDSC, M2 macrophages, whereas they restrain the activation of immune effector cells (Teffs). The metabolic reset operated by tumor cells (i.e., aerobic glycolysis, up-regulation of lipid/amino acid metabolism, etc) allows tumor cells to forestall the limited energetic resources locally available, whereas effector T cells are unable to reset their metabolism and fail the competition to secure the nutrients needed to support their activation. Immune suppressor cells also contribute to brake the immune reactivity of Teffs, that become functionally exhausted. The hypoxic and acidic features of the TME also contribute to the genetic and epigenetic instability of tumor cells promoting clonal evolution and immune escape. Many of the metabolic alterations summarized in this Figure have also been reported in the BM of MM patients.