SPPL3 (Signal Peptide Peptidase Like 3) is an intramembrane-cleaving aspartic protease that regulates cellular glycosylation and immune responses through proteolytic cleavage of type II membrane proteins. SPPL3 acts as a sheddase by cleaving glycan-modifying enzymes including glycosyltransferases (MGAT1/2, B4GALT5) and glycosidases in or near their transmembrane domains, leading to their secretion from the Golgi apparatus 1. This proteolytic activity is essential for maintaining proper glycosylation patterns on cell surfaces. Loss of SPPL3 results in accumulation of glycosyltransferases and altered glycosphingolipid repertoires, particularly increased neolacto-series glycolipids and poly-LacNAc extensions on N-glycans 23. These glycan changes create a 'glycan shield' that sterically impedes antibody and receptor interactions with HLA class I molecules, reducing CD8+ T cell activation and enabling immune evasion 24. Clinically, SPPL3 deletion has been exploited in allogeneic CAR-T cell therapy to prevent graft rejection while maintaining therapeutic efficacy 4. The protease also influences natural killer cell-mediated cytotoxicity, with SPPL3-deficient cells showing resistance to NK cell lysis through glycan-mediated evasion mechanisms 3. Additionally, SPPL3 disruption correlates with poor survival in glioma patients, highlighting its potential as a therapeutic target 2.