Major Histocompatibility Complex Class I-Related Chain A (MICA), Major Histocompatibility Complex Class I-Related Chain B (MICB), and UL16-Binding Proteins (ULBP1-6) (NKG2D Ligands)

NKG2D ligands are a family of stress-induced cell surface molecules, structurally related to MHC class I, that are upregulated on cells undergoing transformation, infection, or other stress. In humans, the main members are MICA, MICB, and UL16-binding proteins (ULBP1–6). These ligands are recognized by the activating immune receptor NKG2D, found on γδ T cells, NK cells, and CD8^+^ T cells. Their engagement triggers cytotoxicity and cytokine release, contributing to antitumor immunity. Tumors frequently adapt by shedding these ligands or downregulating their expression to evade immune attack, yet pharmacological enhancement of their surface expression is a promising immunotherapeutic strategy.

Other names

NKG2D ligandsStress-induced ligandsMICA/MICBUL16-binding proteins (ULBP1–6)Rae-1, Mult1, H60 (mouse homologs)

Upregulation of ligand expression to improve immune recognition Epigenetic modulation to maintain ligand surface expression Inhibition of ligand shedding to prevent immune evasion Stimulation of cytotoxicity via NKG2D receptor signaling