EGFR TKIs suppress MUC1 glycosylation through the PI3K/AKT/SP1/C1GALT1 pathway to enhance TnMUC1 CAR-T efficacy in EGFR-mutant NSCLC.

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for EGFR-mutant cancer (non-small cell lung cancer [NSCLC]), achieving an objective response rate (ORR) of approximately 60%-70%. However, optimizing their therapeutic efficacy remains a challenge. NSCLC cells express the tumor-specific hypoglycosylated Thomsen-nouvelle (Tn) mucin 1 (MUC1) antigen, making them suitable targets for TnMUC1 chimeric antigen receptor (CAR)-T cell therapy. This study shows that EGFR TKIs enhance the efficacy of TnMUC1 CAR-T cell therapy in EGFR-mutant NSCLC, both in vitro and in vivo. EGFR TKIs upregulate TnMUC1 by reducing MUC1 glycosylation, thereby improving TnMUC1 CAR-T cell recognition and cytotoxicity. Specifically, EGFR TKIs modulate TnMUC1-related glycosyltransferases, with core1-beta1,3-galactosyltransferase 1 (C1GALT1) identified as a key enzyme downregulated by EGFR TKIs, suggesting C1GALT1 as a potential therapeutic target.