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

## TL;DR

This study shows that targeting DDOST can make liver cancer cells more responsive to lenvatinib and immunotherapy by disrupting key signaling pathways.

## Contribution

The study identifies DDOST as a novel therapeutic target in HCC that enhances lenvatinib and immunotherapy efficacy.

## Key findings

- DDOST knockdown reduces HCC cell proliferation and increases lenvatinib sensitivity.
- DDOST depletion impairs EGFR glycosylation and downstream signaling pathways.
- OST inhibitors like NGI-1 improve antitumor effects when combined with lenvatinib and immunotherapy.

## 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.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), is a major global health issue. Despite advances in treatment, many patients develop resistance to drugs such as lenvatinib, a common therapy. Researchers explored how a protein called DDOST might contribute to this resistance. They studied HCC cells and found that DDOST is often overactive in these cancers, helping the cancer cells survive and resist treatment. By reducing DDOST activity, they observed that cancer cells became more sensitive to lenvatinib. This was because DDOST affects a process called N-glycosylation, which is crucial for the activity of proteins such as EGFR and PD-L1 involved in cancer growth and immune evasion. The study suggests that targeting DDOST could improve the effectiveness of existing treatments for HCC. In the future, therapies that inhibit DDOST might enhance the response to both lenvatinib and immunotherapy.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.