Affiliations
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- State Key Laboratory of Organ Failure Research, Guangzhou, 510515, China.
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, 510515, China.
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. liuli@i.smu.edu.cn.
- State Key Laboratory of Organ Failure Research, Guangzhou, 510515, China. liuli@i.smu.edu.cn.
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, 510515, China. liuli@i.smu.edu.cn.
PMID: 37204655 DOI: 10.1007/s12072-023-10544-7
Abstract
Background: Lowered nicotinamide adenine dinucleotide (NAD+) levels in tumor cells drive hyperprogression during immunotherapy. Lenvatinib, a first-line treatment for unresectable hepatocellular carcinoma (HCC), can target NAD+ metabolism and influence tumor progression and immune cell activity.
Methods: Metabolites were analyzed using LC-MS/MS and UHPLC-MRM-MS. In vivo and in vitro models validated the effects on NAD+ metabolism, immune cell activity, and interactions between HCC and macrophages.
Results: Lenvatinib increased NAD+ levels, promoted HCC apoptosis, and modulated macrophage polarization from M2 to M1 by targeting TET2 and altering metabolite profiles, thus suppressing HCC progression.
Conclusions: Lenvatinib-TET2 pathway drives NAD+ metabolism changes, enhancing immune response and providing potential therapeutic options for HCC patients with specific NAD+ or TET2 profiles.
Keywords
Hepatocellular carcinoma; Lenvatinib; Macrophage polarization; NAD+ metabolism; TET2.
