Charging CAR by electrostatic power

Summary Chimeric antigen receptor (CAR)‐T cell therapy has emerged as a promising approach for cancer treatment. CAR is a synthetic immune receptor that recognizes tumor antigen and activates T cells through multiple signaling pathways. However, the current CAR design is not as robust as T cell receptor (TCR), a natural antigen receptor with high sensitivity and efficiency. TCR signaling relies on specific molecular interactions, and thus electrostatic force, the major force of molecular interactions, play critical roles. Understanding how electrostatic charge regulates TCR/CAR signaling events will facilitate the development of next‐generation T cell therapies. This review summarizes recent findings on the roles of electrostatic interactions in both natural and synthetic immune receptor signaling, specifically that in CAR clustering and effector molecule recruitments, and highlights potential strategies for engineering CAR‐T cell therapy by leveraging charge‐based interactions.