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

γδ and αβ CAR-T cells show similar cytotoxicity but differ significantly in metabolic and signaling pathways, with γδ cells exhibiting lower glycolytic and oxidative capacities.

• Why it matters: Understanding these differences is crucial because most CAR constructs are optimized for αβ T cells, potentially limiting the effectiveness of γδ T-cell therapies and necessitating tailored engineering approaches.
• What they did: The study conducted a systematic comparison of γδ and αβ T cells transduced with a PSCA-targeting CAR, including phosphoproteomic analysis and functional validation of metabolic and signaling pathways, identifying key differences and potential targets.
• The result: Findings reveal that γδ CAR-T cells have reduced metabolism and weaker AP-1 activation, but engineering strategies like a synthetic costimulatory receptor can enhance their persistence and therapeutic potential.