Amino acid metabolism in hematologic malignancies and the era of targeted therapy

Tumor cells rewire metabolic pathways to adapt to their increased nutritional demands for energy, reducing equivalents, and cellular biosynthesis. Alternations in amino acid metabolism are 1 modality for satisfying those demands. Amino acids are not only components of proteins but also intermediate metabolites fueling multiple biosynthetic pathways. Amino acid-depletion therapies target amino acid uptake and catabolism using heterologous enzymes or recombinant or engineered human enzymes. Notably, such therapies have minimal effect on normal cells due to their lower demand for amino acids compared with tumor cells and their ability to synthesize the targeted amino acids under conditions of nutrient stress. Here, we review novel aspects of amino acid metabolism in hematologic malignancies and deprivation strategies, focusing on 4 key amino acids: arginine, asparagine, glutamine, and cysteine. We also present the roles of amino acid metabolism in the immunosuppressive tumor microenvironment and in drug resistance. This summary also offers an argument for the reclassification of amino acid-depleting enzymes as targeted therapeutic agents.