• CAR and TCR signaling architectures differ fundamentally, with CARs bypassing MHC restriction but exhibiting distinct signaling dynamics that impact solid tumor efficacy.
• Solid tumors present barriers including poor trafficking, immunosuppressive TME, metabolic competition, and antigen heterogeneity, limiting CAR-T effectiveness.
• Engineering strategies such as optimized receptor clustering, ITAM modulation, and novel co-stimulatory domains are being developed to enhance CAR-T function in solid tumors.
• Synthetic biology tools and epigenetic reprogramming offer promising avenues for tunable and persistent CAR-T responses, narrowing the liquid-solid tumor efficacy gap.