GMPS promoting tumor immune evasion by regulating the glycosylation modification of PD-L1

ABSTRACT: Hepatocellular carcinoma (HCC) is a malignant tumor characterized by rapid progression, whose development is attributed to severe immune evasion. Here, we conducted proteomic and scRNA-Seq analysis on advanced HCC tissues and identified a significant molecule, Guanine monophosphate synthase (GMPS). We found that GMPS was closely associated with the immune evasion of HCC. Further investigation revealed that GMPS increased PD-L1 expression by regulating its ubiquitination and glycosylation modification. Mechanistically, GMPS enhanced the bond between PD-L1 and the catalytic subunit STT3A of oligosaccharyltransferase (OST) through acting as an additional module connecting the Sec61 channel complex and STT3A, which aided in the translocation and modification of nascent peptides. The increased PD-L1 impaired the tumor-killing function of CD8+ T cells, ultimately leading to immune evasion. Importantly, targeting GMPS with angustmycin A, an inhibitor of GMPS activity, significantly suppressed PD-L1 expression and tumor growth in HCC, which also increased sensitivity to anti-CTLA-4 immunotherapy. These findings suggested the potential of targeting GMPS as a promising therapeutic approach for HCC.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Xinyu Guo  

LAB HEAD: Xinyu Guo

PROVIDER: PXD045485 | Pride | 2026-05-25

REPOSITORIES: Pride