N-glycosylation stabilizes CD155 to evade NK cell surveillance in colorectal cancer

Abstract

The majority of patients with colorectal cancer (CRC) fail to respond to anti-PD-1/PD-L1 immunotherapy, highlighting an urgent need for alternative immunotherapeutic targets. The immunosuppressive ligand CD155 potently dampens natural killer (NK) cell cytotoxicity via inhibitory receptors, but how CRC cells sustain high CD155 surface levels remains elusive. Here, we identify aberrant CD155 N-glycosylation as a critical driver of CRC immune evasion. We find that the glycosyltransferase STT3A contributes to N-glycosylation of CD155. This modification is essential for maintaining CD155 protein stability, thereby sustaining its surface expression to suppress NK cell-mediated antitumor immunity. Consistent with a role for N-glycosylation in maintaining CD155 expression, pharmacological inhibition of oligosaccharyltransferase activity with NGI-1 promotes CD155 turnover, effectively abrogating its immunosuppressive function and enhancing NK cell-mediated tumor clearance in vivo. Collectively, these findings implicate the STT3A-CD155 glycosylation axis as a therapeutic vulnerability, providing a mechanistic rationale for reprogramming the immunosuppressive CRC microenvironment.