01
Chronic Hepatitis B (CHB) affects over 257 million people globally, leading to significant mortality from cirrhosis and hepatocellular carcinoma (HCC). Current therapies suppress viral replication but cannot fully eliminate infection due to persistent cccDNA in hepatocytes, making functional cure (loss of HBsAg) the primary clinical goal. This study used single-cell, multi-modal profiling to analyze immune and pathological cell states in liver biopsies and peripheral blood of CHB patients compared to those achieving functional cure (FC). The results revealed sustained low viral loads in FC patients, along with the presence of MHC class II-expressing hepatocytes as accessory antigen-presenting cells. Alterations in adaptive immunity were observed, including the emergence of CD4+ cytotoxic T cells (CD4-CTLs) and adaptive memory-like NK cells. Increased neutrophil recruitment in the liver suggested a low-grade immune-active state in FC, while residual low levels of cccDNA and pgRNA potentially influenced adaptive immune re-education. Notably, intrahepatic immune changes were not always reflected in peripheral circulation.These findings provide critical insights into the immune mechanisms underlying functional cure in CHB, offering potential directions for new therapeutic strategies and improved clinical management.
DOI: 10.1016/j.jhep.2024.02.017
02
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited therapeutic options, partly due to its reliance on glutamine to support tumor growth and metabolic processes. This study explores the potential of 6-diazo-5-oxo-L-norleucine (DON), a glutamine metabolism inhibitor, as a therapeutic agent for PDAC. The research demonstrates that DON significantly suppresses tumor growth and metastasis in PDAC models. Mechanistic investigations reveal that DON inhibits the activity of asparagine synthetase (ASNS), resulting in decreased asparagine production, while the reintroduction of asparagine counteracts DON’s effects. In response to DON treatment, PDAC cells upregulate ASNS expression as an adaptive mechanism, with higher ASNS levels correlating with reduced treatment efficacy. Importantly, combining DON with L-asparaginase (ASNase), which depletes asparagine, enhances the anti-tumor effects and significantly reduces metastasis. These findings underscore the critical role of glutamine and asparagine metabolism in PDAC progression and highlight the potential of co-targeting these pathways as a novel therapeutic strategy.
DOI: 10.1038/s43018-023-00649-1
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Editor & Reviewer: Yanwen Zhu
