CAR-dependent and CAR-independent killing mechanisms of CAR T cells. Three pathways may be used by CAR T cells to kill their target. A–C, The perforin/granzyme pathway (granzyme/perforin; A), the death receptor pathway (FasL/Fas, TRAIL/TRAIL-R1/2, and TNFα/TNFR1; B), and the cytokine pathway (IFNγ; C). The perforin/granzyme pathway is dependent on target antigen recognition by CAR, whereas the death receptor and the cytokine pathways could mediate cytotoxicity independently of this specific recognition (dashed arrow). Indeed, CAR T cells may be activated by antigen-positive tumor cells and then induce bystander killing of antigen-negative tumor cells through the death receptor and the cytokine pathways.