Fig. 4.

Mechanisms of hypoxia-sensitive CAR T activation. Representation of the selective activation of the hypoxia-sensitive CAR T cells able to better discriminate tumor cells from healthy cells by exploiting the hypoxia of  the tumor microenvironment. The coding sequence of the CAR has been engineered, introducing nine repeats of HRE in the promoter and an ODD sequence in the C-end of the CAR. Thus, the expression of the hypoxiCAR is enhanced at low oxygen pressure being under the control of HIF-1α/HIF-1β (upper panel). In addition, the presence of the ODD domain guarantees a post-translational control on the hypoxiCAR stability, being degraded at normal oxygen pressure (low panel) or stabilized and exposed on the plasma membrane in hypoxic conditions (upper panel). The figure was created with Biorender.com