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The signaling domain of a tumor antigen-specific chimeric antigen receptor (CAR) is a crucial component responsible for transducing signals upon antigen recognition. It typically comprises a combination of intracellular signaling domains, such as CD3ζ (for primary activation), CD28 or 4-1BB (for costimulation), and potentially OX40, to optimize T cell activation, proliferation, persistence, and anti-tumor efficacy. The specific combination of these domains can significantly impact the potency, durability, and safety profile of CAR-T cell therapies.
Upon antigen binding, the CAR signaling domain initiates T cell activation through ITAM phosphorylation (CD3ζ), enhances proliferation and cytokine secretion (CD28), and promotes long-term survival/persistence (OX40).
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