A study published in *Nature* (2017) demonstrates that targeting a chimeric antigen receptor (CAR) to the T-cell receptor alpha constant (TRAC) locus using CRISPR/Cas9 enhances tumor rejection in a mouse model of acute lymphoblastic leukemia. The TRAC-CAR T cells showed uniform expression, increased potency, and reduced tonic signaling compared to conventional CAR T cells. The study found that TRAC-CAR T cells maintained a more naive and central memory T-cell phenotype, delayed differentiation and exhaustion, and achieved better tumor control. The CAR expression was tightly regulated, with efficient targeting to the TRAC locus, leading to precise and consistent CAR expression. The study also showed that TRAC-CAR T cells outperformed conventional CAR T cells in terms of anti-tumor activity, tumor control, and T-cell function. The findings highlight the potential of CRISPR/Cas9 genome editing to improve immunotherapies by enabling precise and efficient gene targeting. The study also demonstrated that CAR expression levels and promoter strength significantly influence T-cell function, with TRAC-CAR T cells showing superior performance due to their balanced transcriptional response and reduced tonic signaling. The study provides insights into CAR immunobiology and underscores the importance of precise gene targeting for effective immunotherapy.A study published in *Nature* (2017) demonstrates that targeting a chimeric antigen receptor (CAR) to the T-cell receptor alpha constant (TRAC) locus using CRISPR/Cas9 enhances tumor rejection in a mouse model of acute lymphoblastic leukemia. The TRAC-CAR T cells showed uniform expression, increased potency, and reduced tonic signaling compared to conventional CAR T cells. The study found that TRAC-CAR T cells maintained a more naive and central memory T-cell phenotype, delayed differentiation and exhaustion, and achieved better tumor control. The CAR expression was tightly regulated, with efficient targeting to the TRAC locus, leading to precise and consistent CAR expression. The study also showed that TRAC-CAR T cells outperformed conventional CAR T cells in terms of anti-tumor activity, tumor control, and T-cell function. The findings highlight the potential of CRISPR/Cas9 genome editing to improve immunotherapies by enabling precise and efficient gene targeting. The study also demonstrated that CAR expression levels and promoter strength significantly influence T-cell function, with TRAC-CAR T cells showing superior performance due to their balanced transcriptional response and reduced tonic signaling. The study provides insights into CAR immunobiology and underscores the importance of precise gene targeting for effective immunotherapy.