The study explores the potential of naturally occurring mutations in T cells to enhance the efficacy of adoptive T cell therapies. By screening 71 mutations from T cell neoplasms, the researchers identified a gene fusion, CARD11–PIK3R3, which significantly improves T cell signaling, cytokine production, and in vivo persistence in tumors. This fusion enhances the CARD11–BCL10–MALT1 (CBM) complex signaling, leading to increased NF-κB and AP-1 transcriptional activity and MALT1 proteolytic activity. In vitro and in vivo experiments demonstrated that CARD11–PIK3R3-expressing T cells show enhanced anti-tumor activity, reduced T cell dose requirements, and improved persistence without evidence of malignant transformation. The findings suggest that exploiting naturally occurring mutations could be a promising approach to improve T cell therapies for cancer.The study explores the potential of naturally occurring mutations in T cells to enhance the efficacy of adoptive T cell therapies. By screening 71 mutations from T cell neoplasms, the researchers identified a gene fusion, CARD11–PIK3R3, which significantly improves T cell signaling, cytokine production, and in vivo persistence in tumors. This fusion enhances the CARD11–BCL10–MALT1 (CBM) complex signaling, leading to increased NF-κB and AP-1 transcriptional activity and MALT1 proteolytic activity. In vitro and in vivo experiments demonstrated that CARD11–PIK3R3-expressing T cells show enhanced anti-tumor activity, reduced T cell dose requirements, and improved persistence without evidence of malignant transformation. The findings suggest that exploiting naturally occurring mutations could be a promising approach to improve T cell therapies for cancer.