CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.

γδ and αβ CAR-T cells show comparable cytotoxicity but differ phenotypically, with γδ cells exhibiting lower glycolytic and oxidative phosphorylation capacities.

• Why it matters: Understanding these differences is crucial because most CAR constructs are optimized for αβ T cells, yet γδ T cells may require tailored designs for optimal therapeutic function, addressing a gap in personalized immunotherapy.
• What they did: The study conducted a systematic comparison of γδ and αβ T cells transduced with a PSCA-targeting CAR, including phosphoproteomic analysis of 307 phosphosites and pathway enrichment, alongside functional validation and receptor engineering.
• The result: γδ CAR-T cells' lower metabolic activity and weaker AP-1 activation suggest targets like TXNIP could enhance their function, leading to improved in vivo persistence and informing cell type-specific receptor strategies.