Scientists from Prince of Songkla University investigated the intrinsic transcriptional gene underlying the functional advantage of CD19.79A.40z CAR-T cells following CD19 antigen exposure using transcriptome analysis compared to CD28 or 4-1BB. The results showed that CD19.79A.40z CAR-T cells up-regulated genes involved in T-cell activation, T-cell proliferation, and NF-κB signaling, whereas down-regulated genes associated with T-cell exhaustion and apoptosis. Interestingly, CD19.79A.40z CAR- and CD19.BBz CAR-T cells were enriched in almost similar pathways. The gene set enrichment analysis demonstrated the enrichment of genes, which were previously identified to correlate with T-cell proliferation, interferon signaling pathway, and naïve and memory T-cell signatures, and down-regulated T-cell exhaustion genes in CD79A/CD40, compared with the T-cell costimulatory domain. The CD19.79A.40z CAR-T cells also up-regulated genes related to glycolysis and fatty acid metabolism, which are necessary to drive T-cell proliferation and differentiation compared with conventional CD19CAR-T cells. This study provides a comprehensive insight into the understanding of gene signatures that potentiates the superior antitumor functions by CD19CAR-T cells incorporated with the CD79A/CD40 costimulatory domain.