NKG2D CAR-T cells for solid tumor immunotherapy: advances, challenges, and future directions

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in hematologic malignancies, but its efficacy in solid tumors remains limited, primarily due to the immunosuppressive tumor microenvironment (TME) that hinders CAR-T cell trafficking and function. NKG2D CAR-T cells, which target stress-induced NKG2D ligands (NKG2DLs) broadly expressed on tumor cells, have shown promising potential in overcoming the immunosuppressive barriers of the solid TME. This review highlights recent advances in NKG2D CAR-T cell strategies for solid tumors, including innovations in CAR architecture, signaling pathway engineering, combination immunotherapy, and the development of armored CAR constructs. We further discuss the therapeutic potential, current challenges, and future directions of these approaches to inform the design of more effective and durable CAR-T cell therapies for solid tumors.