Next-Generation CAR Design: Current Status and Challenges

CAR receptor engineering has progressed from “add a costimulatory domain” to a disciplined, multi-parameter design problem spanning extracellular geometry, intracellular network wiring, and safety control layers. Using the provided schematic of CAR generations (Figure 1) as a conceptual anchor, this mini-review summarizes the current state of CAR design from first-generation ITAM-only receptors to armored/TRUCK concepts and cytokine-receptor/JAK–STAT–coupled “fifth-generation” constructs. TRUCK designs formalized the principle of antigen-triggered payload delivery to reshape the tumor microenvironment. Fifth-generation architectures exemplified by IL-2Rβ/STAT-recruiting CARs attempt to integrate activation, costimulation, and STAT transcriptional programming in an antigen-dependent manner. We highlight design variables that often dominate in vivo behavior yet are underappreciated in “generation” shorthand: hinge/spacer and transmembrane selection, Fc receptor interactions, receptor clustering/tonic signaling, and exhaustion dynamics influenced by CD28 versus 4-1BB signaling. Finally, we frame NKG2D-based CAR approaches as a case study where target biology forces architectural choices (multi-ligand recognition, endogenous adaptor signaling, fratricide risk and ligand dynamics), illustrating how modern CAR design must be co-developed with biomarker strategy and control mechanisms to achieve a favorable therapeutic index.