Fig. 1

Structure of endogenous chimeric antigen receptors used in NK cell adoptive therapies. A NK cells harbor different activating or inhibitory receptors that directly contain activating (green) or inhibitory domains (red) or are associated with coreceptors required for signaling, such as DAP10/12 or CD3ζ. B Several generations of CAR constructs with recognition domains fused to transmembrane domains and intracellular signaling domains have been designed. Depending on the generation, one or multiple intracellular domains can be combined (either based on T-cell receptor domains or specifically derived from NK cell receptors to activate cells and enhance functionality). In the fourth generation, a transgene encoding cytokines is also inserted and placed under the regulation of an NFAT-sensitive promoter, which is activated upon recognition of the antigen by the CAR construct. C Logic-gated synthetic circuits, such as dual CARs or inhibitory CARs, have been combined in CAR-NK cells. Innovative approaches, including adapter CARs and Syn/notch receptors, are also compatible with the use of NK cells