Fig. 4

Chimeric antigen receptors (CARs) of the first, second, and third generations, as well as CAR NK cell-based immunotherapy, are depicted schematically. Synthetic extracellular receptors for target antigen recognition, a transmembrane domain, and one intracellular signaling domain are all present in first-generation CAR molecules. For enhanced signaling, second and third-generation CAR constructions are equipped with one or more intracellular co-stimulatory domains. A constitutive or inducible expression cassette for a transgenic protein is a further modification made to fourth generation CARs (also known as TRUCKs (T cells redirected for antigen-unrestricted cytokine-initiated killing)). Upon CAR antigen identification, fourth-generation CARs can activate downstream transcription factors, such as nuclear factor of activated T cells (NFAT), leading to the production of cytokines