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Perez CR, Garmilla A, Nilsson A, Baghdassarian HM, Gordon KS, Lima LG, Smith BE, Maus MV, Lauffenburger DA, Birnbaum ME
Cell Syst 16 (5) 101260 [2025-05-21; online 2025-04-10]
The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function-particularly at the molecular level-are lacking. Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures. Informed by these observations, we functionally characterize transcriptionally distinct ICD variants across various contexts to build comprehensive maps from ICD composition to phenotypic output. We identify a unique tonic signaling signature associated with a subset of ICD architectures that drives durable in vivo persistence and efficacy in liquid, but not solid, tumors. Our findings work toward decoding CAR signaling design principles, with implications for the rational design of next-generation ICD architectures optimized for in vivo function.
PubMed 40215972
DOI 10.1016/j.cels.2025.101260
Crossref 10.1016/j.cels.2025.101260
mid: NIHMS2074196
pmc: PMC12097926
pii: S2405-4712(25)00093-6