The tonic signaling of pre-BCR and pre-TCR is necessary for the survival and development of lymphocytes.24 Consistent with this, the inefficient antigen-independent tonic signaling was also reported to compromise the efficacy of CD22.41BBζ CAR-T cells against acute lymphoblastic leukemia.6 Considering the paradoxical effects of tonic signaling in effector functions of CAR-T cells against solid tumors and hematologic malignancies, we hypothesized that both too high and too low levels of tonic signaling would impair the CAR-T fitness. This evidence concerns the gene CD22 and acute lymphoblastic leukemia.