Immunomodulatory impact of α-fetoprotein

α-Fetoprotein (AFP) is a fetal glycoprotein produced by most human hepatocellular carcinoma tumors. Research has focused on its immunosuppressive properties in pregnancy, autoimmunity, and cancer, and human AFP directly limits the viability and functionality of human natural killer (NK) cells, monocytes, and dendritic cells (DCs). AFP-altered DCs can promote the differentiation of naïve T cells into regulatory T cells. These properties may work to shield tumors from the immune system. Recent efforts to define the molecular characteristics of AFP identified key structural immunoregulatory domains and bioactive roles of AFP-bound ligands in immunomodulation. We propose that a key mechanism of AFP immunomodulation skews DC function through cellular metabolism. Delineating differences between fetal 'normal' AFP (nAFP) and tumor-derived AFP (tAFP) has uncovered a novel role for tAFP in altering metabolism via lipid-binding partners.