Fig. 1.

Evolution of chimeric antigen receptor (CAR)-NK cell structure over time: The structural components of the 1st, 2nd, 3rd, 4th and 5th generation of CAR. The number and composition of intracellular activation domains determines CAR generation. Various combinations of activating domains are used to mount a strong antitumor response. One example of a “fourth-generation” CAR is shown, coexpressing stimulating cytokines or chemokines. The 5th CAR generation or next is based on the second generation CAR, but they contain a truncated cytoplasmic IL-2 receptor β-chain domain with a transcription factor STAT3 binding site. The different CAR generations are designed to further improve the therapeutic activity of the CAR-based immunotherapies. Abbreviations: scFv, single-chain variable fragment; TM, transmembrane.