GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328715/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328715GEOGSEfalseCell autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysisWe 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 knock-in 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.2026/04/26GSE328715GSM9688120GSM9688100GSM9688121GSM9688102GSM9688101GSM9688104GSM9688103GSM9688106GSM9688105GSM9688108GSM9688107GSM9688109GSM9688098GSM9688097GSM9688111GSM9688110GSM9688099GSM9688113GSM9688112GSM9688115GSM9688114GSM9688117GSM9688116GSM9688119GSM968811834284328715Homo sapiens