The amino acid transporters SLC38A3-SLC38A5-SLC38A7 as novel anti-cancer therapeutic targets

System N amino acid transporters SLC38A3 and SLC38A5 are carriers capable of mediating net inward or outward fluxes of substrates, such as glutamine, asparagine and histidine, coupled with Na+ symport and H+ antiport. The third member of the group, SLC38A7, principally exports glutamine and asparagine from lysosomes and its ion-coupling mechanism remains incompletely defined. Although historically less investigated than other amino acid transporters, emerging evidence reveals that System N carriers play diverse and context-dependent roles across several solid tumors and hematological malignancies. SLC38A3 can exert pro-tumor or tumor suppressive activities, displaying bidirectional transport and lineage-specific regulatory functions. SLC38A5 sustains macropinocytosis, pro-growth pathways, and antioxidant stress response conferring ferroptosis resistance. In addition, when expressed on stromal cells, it promotes amino acid exchanges within tumor microenvironment. SLC38A7 is expressed on lysosomal membranes to export proteolysis-derived amino acids and activates growth signaling. Together, evidence thus far available indicates that these transporters support metabolic plasticity, tumor progression, therapy resistance and microenvironmental remodeling in many types of cancers. This review summarizes recent advances in the comprehension of expression, regulation and functional relevance of System N transporters, highlighting their metabolic role in cancer and discussing their possible exploitation as emerging therapeutic targets.