This article describes a study that demonstrates the enhanced efficacy of CAR T cells when the CAR is targeted to the T-cell receptor alpha constant (TRAC) locus using CRISPR/Cas9 genome editing. The researchers developed a CD19-specific CAR (1928z) that was integrated into the TRAC locus, which resulted in uniform CAR expression in human peripheral blood T cells and improved T-cell potency. These TRAC-CAR T cells outperformed conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. The study also showed that targeting the CAR to the TRAC locus prevented tonic CAR signaling and enabled effective internalization and re-expression of the CAR following antigen exposure, delaying T-cell differentiation and exhaustion. These findings highlight the potential of CRISPR/Cas9 genome editing to enhance immunotherapy by improving CAR function and reducing off-target effects. The study further demonstrated that the level of CAR expression is critical for T-cell function, with higher expression leading to increased tonic signaling and accelerated differentiation. The researchers also showed that targeting the CAR to the TRAC locus resulted in a more balanced transcriptional response, allowing for optimal recovery of CAR expression after antigen engagement. These results suggest that precise targeting of CAR expression to specific genomic loci can significantly improve the therapeutic potency of CAR T cells. The study also highlights the importance of understanding CAR immunobiology and the potential of genome editing to advance T-cell therapies.This article describes a study that demonstrates the enhanced efficacy of CAR T cells when the CAR is targeted to the T-cell receptor alpha constant (TRAC) locus using CRISPR/Cas9 genome editing. The researchers developed a CD19-specific CAR (1928z) that was integrated into the TRAC locus, which resulted in uniform CAR expression in human peripheral blood T cells and improved T-cell potency. These TRAC-CAR T cells outperformed conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. The study also showed that targeting the CAR to the TRAC locus prevented tonic CAR signaling and enabled effective internalization and re-expression of the CAR following antigen exposure, delaying T-cell differentiation and exhaustion. These findings highlight the potential of CRISPR/Cas9 genome editing to enhance immunotherapy by improving CAR function and reducing off-target effects. The study further demonstrated that the level of CAR expression is critical for T-cell function, with higher expression leading to increased tonic signaling and accelerated differentiation. The researchers also showed that targeting the CAR to the TRAC locus resulted in a more balanced transcriptional response, allowing for optimal recovery of CAR expression after antigen engagement. These results suggest that precise targeting of CAR expression to specific genomic loci can significantly improve the therapeutic potency of CAR T cells. The study also highlights the importance of understanding CAR immunobiology and the potential of genome editing to advance T-cell therapies.