Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function
Year: 2026
Type: article
Abstract: Human protein-coding genes evolved via rearrangement of domains from ancestral genes. We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding. Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families. Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.
Source: Cell
Authors: Oliver Takacsi-Nagy, Sivakanthan Kasinathan, Austin Hartman, Yajie Yin, Lujing Wu, Andy Y. Chen, Laura M. Moser, Audre P. May, Gabriella C. Reeder, Emily Celallos Fuentes, Courtney Kernick, Johnathan Lu, Alison K. McClellan, Colin J. Raposo, Brendan Terrall, Nicole E. Theberath, Patrick K. Yan, Peng Xu, Elena Sotillo, Justin Eyquem, Crystal L. Mackall, Theodore L. Roth, Ansuman T. Satpathy
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Burroughs Wellcome Fund, Cancer Research Institute, Arthritis National Research Foundation, Lupus Foundation of America, Stanford University, Rheumatology Research Foundation, Lupus Research Alliance, Parker Institute for Cancer Immunotherapy, Mark Foundation For Cancer Research, Childhood Arthritis and Rheumatology Research Alliance, National Institutes of Health, University of California, San Francisco, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Stanford Maternal and Child Health Research Institute
OpenAlex ID: W7203764798