Targeting NKG2D/NKG2DL axis in cancer immunotherapy: mechanisms and therapeutic applications

The natural killer group 2, member D (NKG2D) receptor, a critical activating or co-stimulatory receptor expressed on natural killer and T cells, mediates anti-tumor immune responses by recognizing NKG2D ligands (NKG2DLs) with aberrant expression on tumor cells. However, tumors have developed multiple strategies to evade NKG2D-mediated immune surveillance, including the downregulation of NKG2DLs, proteolytic shedding that generates soluble NKG2DLs (sNKG2DLs), and sNKG2DL-driven remodeling of the tumor microenvironment toward an immunosuppressive state. Consequently, therapeutically harnessing the NKG2D/NKG2DL axis to eradicate tumor cells while overcoming immune escape has become a central focus of current research and clinical translation. Emerging strategies include pharmacologic upregulation of NKG2DLs, monoclonal antibodies that reduce ligand shedding and neutralize sNKG2DLs, T/NK-cell engagers that redirect cytotoxicity, and adoptive cellular therapies capable of selective tumor cell elimination. Early-phase clinical studies of NKG2D/NKG2DL-targeted therapeutic strategies have generally demonstrated an acceptable safety profile; however, objective response rates remain modest, and the durability of response is often limited. Key challenges to clinical translation include on-target/off-tumor toxicity, pronounced NKG2DL heterogeneity and plasticity, and a lack of predictive biomarkers. Accordingly, future directions should prioritize the rational integration of these modalities, the optimization of engineered cell therapies to balance efficacy with safety, and the identification of suitable biomarkers for patient stratification. Here, we summarize the expression patterns and functional roles of the NKG2D/NKG2DL axis and discuss the mechanisms by which this pathway contributes to tumor immune escape. We further review strategies to modulate or target the axis, highlight recent clinical advances, and discuss opportunities and challenges for clinical translation.