Back Article

Figure 1. 

Complementary target spaces and receptor architectures of CAR-T and TCR-T cells. (a) Conventional CARs directly recognize intact extracellular epitopes, surface proteins, glycoepitopes, and glycolipids, independently of HLA, but are confined to the plasma-membrane proteome, generally require relatively high antigen density, and face escape through antigen loss or low antigen density. TCRs recognize peptide-MHC complexes generated from a much broader source proteome through antigen processing and MHC presentation, reaching intracellularly derived oncoproteins at very low ligand density, at the cost of HLA restriction, low pMHC abundance, presentation loss, and cross-reactivity risk. (b) A CAR fuses recognition and signaling into a single chain (scFv, hinge and transmembrane segment, one costimulatory domain, and CD3ζ), whereas the TCR distributes these functions across the αβ heterodimer and the associated CD3γε, CD3δε, and CD3ζζ modules. Both nonetheless converge on the same signaling machinery: Lck-mediated phosphorylation of CD3ζ ITAMs, ZAP-70, the LAT/SLP-76 signalosome, and PLCγ1, whose products IP₃ and DAG drive the Ca²⁺-calcineurin-NFAT, RasGRP1-RAS-ERK-AP-1, and PKCθ-CBM-IKK-NF-κB pathways.

Figure 2. 

Modality-specific discovery and validation of actionable tumor targets. Shared molecular profiling feeds distinct CAR and TCR target-discovery pipelines: CAR candidates are filtered for surface accessibility, density, heterogeneity, target behavior, and normal-tissue expression, whereas TCR candidates are evaluated for HLA context, predicted and natural pMHC presentation, and tumor selectivity. Both pathways converge on tumor coverage, prevalence and fitness dependence, functional activity, escape risk, and normal-tissue and cross-reactivity safety.

Figure 3. 

Recognition-signaling design space of engineered T-cell platforms. (a) Conventional CARs combine surface-antigen recognition with synthetic signaling, whereas TCRs recognize pMHC through the native TCR-CD3 complex. TCR-mimic CARs and TRuC/STAR/HIT receptors occupy the two hybrid combinations. (b) While ImmTACs represent a soluble pMHC-directed format that recruits endogenous T cells through CD3.

Figure 4. 

Target- and effector-centered failure modes and representative engineering responses. Antigen loss or low density, impaired HLA or antigen presentation, normal-tissue target expression, receptor cross-reactivity or TCR mispairing, and tumor-microenvironment-driven dysfunction can compromise efficacy or safety. Multi-antigen targeting, threshold tuning, alternative recognition strategies, logic gating, specificity and pairing control, and armoring or cell-state reprogramming may mitigate these vulnerabilities, although no strategy is universally effective or free of trade-offs.

Figure 5. 

AI-assisted adaptive targetome workflow. Serial sampling and multi-omic profiling enable repeated mapping of the evolving tumor targetome. Computational prediction and escape forecasting guide target and receptor prioritization, while immunopeptidomic, functional, cross-reactivity, and normal-tissue validation provide experimental ground truth. These outputs inform receptor design and adaptive treatment, but computational models do not replace experimental safety testing.