Fig. 3

Basic structure of CAR and the evolution of CAR design. A The basic CAR structure consists of the extracellular antigen recognition domain (typically scFv), hinge domain, transmembrane domain, and one or more intracellular signaling domains. B The first-generation CARs contain a scFv for single-antigen recognition and subsequent ligation of the hinge domain, a transmembrane domain, and an intracellular CD3ζ for activation signal transmission. C, D The second- and third-generation CARs introduce one and two costimulatory domains separately, usually 4-1BB or CD28, to enhance the proliferation and persistence of CAR-T cells. E Many next-generation CARs have been developed to further enhance the anti-tumor potential of CAR-T cells, mainly including “OR” logic-gated CARs to improve antigen recognition profile a “AND” b “AND-NOT” c logic-gated CARs to improve recognition specificity, adaptor-dependent (d) and pharmacologic switch CARs (e) to enhance controllability, secretion CARs with enhanced anti-tumor ability (f), TME response CARs (g), other modifications of membrane proteins (h), and gene editing CARs (i). scFv, single-chain fragment variable; TM, transmembrane domain; TF, transcription factor; BBIR, biotin-binding immune receptor; rtTA, reverse tetracycline transcriptional activator; ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-depended cytotoxicity; solHVEM, soluble herpes virus entry mediator; HRE, hypoxia response elements; and ODD, oxygen-dependent degradation domain