Induced pluripotent stem cell-derived chimeric antigen receptor natural killer cells: Engineering innovations, translational hurdles and clinical prospects in immune therapy

Figure 5 Schematic diagram of chimeric antigen receptor natural killer cell structural optimization. The figure illustrates key structural modules involved in the optimization of chimeric antigen receptor natural killer (CAR-NK) cells. The antigen-recognition domain can be designed using different binding modules, including a single-chain variable fragment, a binding protein targeting peptide-major histocompatibility complex, or a nanobody, also known as the variable domain of a heavy-chain-only antibody. These antigen-binding modules differ in molecular size, binding properties, hydrophobicity, and potential immunogenicity. The extracellular recognition module is connected to intracellular signaling components through linker, hinge, and transmembrane regions, such as a cluster of differentiation 8 alpha (CD8α) hinge domain and a natural killer group 2 member D transmembrane domain. NK cell-associated surface molecules, including cluster of differentiation 56 (CD56) and CD16, and NK-adapted signaling domains, including DNAX-activating protein 10, 2B4, also known as CD244, and CD3ζ, contribute to CAR-NK cell activation. After target recognition, activated CAR-NK cells mediate cytotoxic attack through effector molecules such as perforin and granzymes. scFv: Single-chain variable fragment; pMHC: Peptide-major histocompatibility complex; CD: Cluster of differentiation; DAP10: DNAX-activating protein 10; NKG2D: Natural killer group 2 member D.