SLC3A2 encodes the heavy chain subunit (4F2hc) of the heteromeric amino acid transporter system xc-, which facilitates the exchange of extracellular cystine for intracellular glutamate 1. The protein functions as a critical regulator of ferroptosis, a form of iron-dependent cell death characterized by lipid peroxide accumulation 1. SLC3A2 enables cystine uptake necessary for glutathione synthesis, which protects cells from ferroptosis by preventing lipid peroxidation 12. The protein's stability and function are regulated by N-glycosylation mediated by glycosyltransferase B3GNT3, which enhances the interaction between 4F2hc and its light chain partner xCT 2. Beyond amino acid transport, SLC3A2 serves as a polyamine transporter, facilitating N1-acetylspermidine efflux in hepatocellular carcinoma 3. In cancer contexts, SLC3A2 promotes immune evasion through multiple mechanisms: it competes with T cells for lysine uptake, impairing T cell proliferation and function 4, and facilitates metabolic reprogramming that drives tumor-associated macrophage polarization toward the immunosuppressive M2 phenotype via arachidonic acid secretion 5. High SLC3A2 expression correlates with poor prognosis in cancer patients and reduced efficacy of immunotherapy 14.