CAR-T cell signaling dynamics, rational design principles and artificial intelligence for next-generation chimeric antigen receptors

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CAR T cell therapy has revolutionized hematologic malignancy treatment but faces challenges in solid tumors and durability.
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CAR signaling is dynamic, requiring different properties for initiation, amplification, and maintenance to avoid exhaustion and toxicity.
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First-generation CARs had limited efficacy due to insufficient signaling, leading to the development of second-generation CARs with costimulatory domains.
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Second-generation CARs, incorporating costimulatory domains like CD28 or 4-1BB, significantly enhance T cell proliferation and clinical efficacy.
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Emerging strategies focus on fine-tuning CAR signaling to balance potency and durability, utilizing high-throughput screening and machine learning.

Frontiers In Immunology

by Xin Liu, Fangjia Tong, Jiayi Zhang, William Gradishar, Huiping Liu, Rongfu Wang
July 8, 2026

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