Fig. 1

Structural design of different generations of CARs. A First-generation CARs with ScFv, Hinge, Transmembrane, and CD3ζ domains. B Second-generation CARs with all first-generation domains and an additional CD28/4-1BB costimulatory domain. C Third-generation CARs with all first-generation domains and two additional costimulatory domains (CD28 and 4-1BB). D Two different types of fourth-generation CARs with additional cytokine and co-stimulatory ligand domains to address challenges of tumor microenvironments. E Fifth-generation CARs with one intracellular domain more than the fourth-generation CAR-T cells, which include truncated intracellular domains of cytokine receptors (e.g., IL-2R chain fragment), with an additional domain for binding transcription factors such as STAT-3/5. CARs, Chimeric antigen receptors; ScFv, single-chain variable fragment