Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis

  • Cell. 2026 Jun 25;189(13):3883-3902.e23. doi: 10.1016/j.cell.2026.04.037.
Jeremy R Bjelajac  1 ,  Adrià Cañellas-Socias  2 ,  Preeti Nehra  3 ,  Kevin Reynolds  3 ,  Meena Malipatlolla  3 ,  Naiara Martinez Velez  3 ,  Diane C Manjarrez  3 ,  Katie Ho  4 ,  Peng Xu  3 ,  Jennifer L Hamad  5 ,  Sean A Yamada-Hunter  6 ,  Louai Labanieh  7 ,  Elena Sotillo  2 ,  Crystal L Mackall  8
Affiliations
  • 1. Stem Cell and Regenerative Medicine Graduate Program, Stanford University School of Medicine, Stanford, CA, USA; Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill West Coast Cancer Hub, Stanford, CA, USA.
  • 2. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill West Coast Cancer Hub, Stanford, CA, USA.
  • 3. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 4. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  • 5. Department of Chemistry, Stanford University, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA.
  • 6. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
  • 7. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8. Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Weill West Coast Cancer Hub, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: [email protected].
PMID: 42143019 DOI: 10.1016/j.cell.2026.04.037
Abstract

We sought to endow T cell autonomous regulation of cell surface protein expression by exploiting the conditional proteolytic activity of ADAM17 following T cell activation. Screening of canonical ADAM17 substrates yielded a minimal 15-aa CD62L-derived motif that confers rapid and reversible cleavage of a receptor following T cell activation-termed activation-induced release (AIR). Embedding AIR into tonic-signaling CARs reduced basal CAR expression proportional to the degree of tonic signaling induced, curtailing exhaustion and improving antitumor potency. In non-tonic signaling CARs, AIR decreased activation-induced cell death and enhanced T cell expansion after stimulation. AIR's modularity supports higher-order logic-gating; AIR-regulated peptide masks enable antigen-dependent unmasking of an EGFR-targeting CAR. Finally, CRISPR knockin of AIR into endogenous FAS or TGFBR2 endowed them with activation-induced shedding, which enhanced tumor clearance while preserving signaling in non-activating conditions. AIR is a compact switch that provides fast, autonomous regulation of surface proteins for next-generation cell therapies.

Keywords
ADAM17; CAR; T cells; bioengineering; cancer; immunotherapy; protease; synthetic biology.
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