NKG2D (Natural Killer Group 2, member D) is an activating receptor expressed in the cytotoxic branch of the immune system, primarily on the surface of Natural Killer (NK), CD8+, and certain subsets of NK-, γδ-, and CD4+ T cells (Raulet, 2023). Its capacity to activate immune effectors without the need for antigen presentation makes the NKG2D receptor a major component of our first-line defense against both neoplastic development and external pathogens.

Despite being encoded by a highly conserved gene, Klrk1, NKG2D associates with a surprisingly wide range of ligands, including MICA, MICB, and six members of the ULBP family. These ligands are normally expressed in very low abundance but can be induced by conditions of cellular stress such as heat shock, bacterial or viral infection, and malignant transformation. Their recognition by NKG2D can directly activate or co-stimulate cytotoxic cells, inducing cytolytic responses to eliminate the damaged cells (Lanier, 2008).

Structurally, NKG2D is composed of a homodimer of two transmembrane proteins linked by disulfide bonds which by themselves lack signaling properties. The pathways activated by NKG2D depend on the recruitment of the adaptor protein DAP10 to mediate downstream signaling effectors, such as AKT and ERK, promoting cell survival, proliferation, and cytotoxic functions in both NK- and CD8+ T cells (Upshaw, 2006).

Downregulation of NKG2B ligands has been observed in a wide range of cancers (Groh, 2002; Thomas, 2008; Zhang, 2023 ) and may be a driver behind the diversification of NKG2B recognition. Another approach is shedding the ligands into the extracellular environment, thereby impairing NK cell recognition and function. Therapeutic strategies aiming to enhance NKG2D-mediated responses, such as monoclonal antibodies, ligand-based therapies, and T or NK cell engineering are currently under investigation to bolster anti-tumor immunity (Leivas, 2021;Verhaar, 2024;Baugh, 2024).