Figure 4. Nitrogen metabolism within the tumor microenvironment.

Nitrogen sources in the form of amino acids are shared by cancer cells, immune cells, endothelial cells, and stromal cells in the tumor microenvironment. Besides free amino acids, the acquisition of nitrogen in the form of extracellular protein (through micropinocytosis) is upregulated in cancer. Ammonia as a nitrogen waste can also be assimilated by the cancer cells from the microenvironment; however, whether such a phenomenon exists in other cell types remains largely unknown. Tumor cells upregulate intracellular catabolism of tryptophan and arginine, depleting their levels in the extracellular space. Depletion of tryptophan and arginine from the local space can inhibit effector CD8⁺ T cells proliferation and function. The catabolic derivative of tryptophan (kynurenine) has been shown to enhance T regulatory cells (Treg) phenotype. Stromal cells that reside in the vicinity of the cancer cells can release alanine through autophagy as well as glutamine through enzyme glutamine synthetase, which can be utilized by the neighboring cancer cells.