Chimeric antigen receptor (CAR)-T cells show a greater propensity to exhaustion. They also tend to induce cytokine-related toxicities at a higher rate than naturally occurring T cells. The former is due to the elevated tonic—or idling, non-antigen induced—signaling by chimeric receptors; the latter by the intense and persistent activation of CAR-T cells upon antigen stimulation. Researchers led by Ludwig Stanford’s Crystal Mackall reported in a May Cell paper a strategy to address these challenges by exploiting protein shedding, an intrinsic mechanism by which cells control the activity of cell surface proteins, including T cell receptors. The researchers inserted a short canonical sequence cut by the protease ADAM17—which kicks into action in T cells upon activation—into the outer, membrane-proximal stretch of the CAR to create an activation-induced release (AIR)-regulated CAR. They show here that CAR levels on the surface of these cells were reduced in proportion to their tonic signaling, curtailing their exhaustion and improving their anti-tumor efficacy. Receptors that suppress immune responses (like TGF-β) or induce cell death (like FAS) following T cell activation could also be equipped with the AIR motif to boost CAR-T cell potency. AIR also permits the design of logic-gated CARs, in which the activation of one CAR leads to the AIR-enabled unmasking of a second CAR at an appropriate site.
Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis
Cell, 2026 May 15