Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies, with limited efficacy of systemic therapies due to poor survival benefit and drug resistance. Dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), a critical component of oligosaccharyltransferase (OST), is upregulated in multiple cancers, yet its role in HCC is unclear. Here we demonstrate that DDOST expression is elevated in HCC tissues and correlated with poor prognosis. Functional studies showed that DDOST knockdown suppressed cell proliferation, induced cell cycle arrest and enhanced their lenvatinib sensitivity both in vitro and in vivo. Mechanistically, DDOST depletion impaired EGFR N-glycosylation, suppressing downstream AKT, ERK5 and ERK1/2 signaling, thereby sensitizing HCC cells to lenvatinib. Loss of DDOST also reduced PD-L1 glycosylation. Furthermore, the OST inhibitor NGI-1 and NGI-1-loaded nanoparticles exerted potent antitumor effects and further augmented the efficacy of lenvatinib and immunotherapy. These findings highlight DDOST as a promising therapeutic target to improve treatment outcomes in HCC.