Furthermore, our results extend these findings by demonstrating that T cell exhaustion and the terminal differentiation state, caused by either tonic signaling or stimulation by tumor antigens, can be prevented or reversed by inhibiting the SOCE‐calcineurin‐NFAT pathway in CAR‐T cells independent of the CAR costimulatory domain (CD28 or 4‐1BB). This evidence concerns the gene CD28 and neoplasm.