The study investigates the enhancement of CAR T cell efficacy in solid tumors by overexpressing the transcription factor FOXO1. CAR T cells, which have shown promise in treating hematological malignancies, struggle in solid tumors due to the immunosuppressive tumor microenvironment. The research team found that overexpression of FOXO1 in CAR T cells derived from healthy donors and patients promoted a stem-like phenotype, improved mitochondrial fitness, persistence, and therapeutic efficacy in vivo. FOXO1 overexpression maintained CAR T cell 'stemness' and enhanced persistence more effectively than other transcription factors upregulated by IL-15, such as TCF7 and ID3. In mouse models, FOXO1-overexpressing CAR T cells exhibited increased polyfunctionality, improved metabolic fitness, and enhanced tumor control compared to control CAR T cells. In human CAR T cells, wild-type FOXO1 overexpression enhanced tumor regression without toxicity, suggesting its potential for clinical application. The study highlights the potential of FOXO1 as a genetic approach to improve CAR T cell efficacy in solid tumors.The study investigates the enhancement of CAR T cell efficacy in solid tumors by overexpressing the transcription factor FOXO1. CAR T cells, which have shown promise in treating hematological malignancies, struggle in solid tumors due to the immunosuppressive tumor microenvironment. The research team found that overexpression of FOXO1 in CAR T cells derived from healthy donors and patients promoted a stem-like phenotype, improved mitochondrial fitness, persistence, and therapeutic efficacy in vivo. FOXO1 overexpression maintained CAR T cell 'stemness' and enhanced persistence more effectively than other transcription factors upregulated by IL-15, such as TCF7 and ID3. In mouse models, FOXO1-overexpressing CAR T cells exhibited increased polyfunctionality, improved metabolic fitness, and enhanced tumor control compared to control CAR T cells. In human CAR T cells, wild-type FOXO1 overexpression enhanced tumor regression without toxicity, suggesting its potential for clinical application. The study highlights the potential of FOXO1 as a genetic approach to improve CAR T cell efficacy in solid tumors.