Beyond Signal Strength: Combining biophysical properties with co-stimulatory signals to design optimal TCRL-based CAR-T cells
To address the limited efficacy of CAR T-cell therapy in solid tumors, we systematically optimized the intracellular signaling domains of TCR-Like (TCRL) CARs targeting melanoma. Our research identifies the advanced 3rd-generation CAR and the dual-signal novel hybrid constructs as lead candidates, demonstrating superior targeted cytotoxicity across varying antigen densities without triggering immediate inhibitory overload. Crucially, transcriptomic analysis reveals these engineered T-cells succeed by reprogramming their genetic profile toward “metabolic intelligence”—prioritizing long-term metabolic fitness over mere signal amplification to prevent exhaustion and sustain anti-tumor activity.
