NKG2D-Based CAR-T Cells for Cancer Immunotherapy: Biological Rationale, Clinical Experience, and Current Challenges

NKG2D is an activating immunoreceptor expressed by natural killer (NK) cells and subsets of T cells that recognizes multiple stress-induced ligands (e.g., MICA/MICB and ULBP1–6) frequently upregulated in malignant transformation. NKG2D signaling in humans is mediated by the DAP10 adaptor and associated downstream nodes (e.g., PI3K and Grb2–Vav1), which collectively control cytotoxic synapse formation and effector function. NKG2D-based CAR-T cells leverage this multi-ligand recognition to broaden tumor coverage and mitigate single-antigen escape, positioning the approach as a potentially “pan-tumor” CAR strategy. Early clinical experience with autologous NKG2D-CAR products has established feasibility and a manageable safety profile in selected settings; however, objective responses have been inconsistent and durability remains limited. A major set of barriers is intrinsic to the NKG2D axis itself: tumors can downregulate ligand expression, shed MICA/MICB via metalloproteases, and accumulate soluble/vesicular ligands that blunt NKG2D function and promote receptor internalization. These mechanisms synergize with tumor microenvironment (TME) suppression, particularly TGF-β–mediated inhibition of NKG2D pathways. This review synthesizes the mechanistic rationale for NKG2D-CAR designs, summarizes representative clinical programs, and focuses on current challenges and practical mitigation strategies: (i) selectivity and safety when stress ligands are inducible in inflamed normal tissues; (ii) ligand shedding and soluble ligand decoy effects; (iii) TGF-β dominance; (iv) persistence/exhaustion constraints; and (v) manufacturing and development considerations.