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  3. Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells

Leptin decreases Th17/Treg ratio to facilitate neuroblastoma via inhibiting long-chain fatty acid catabolism in tumor cells

  • Oncoimmunology. 2025 Dec;14(1):2460281. doi: 10.1080/2162402X.2025.2460281.
Meng Li 1,  Di Li 1,  Hai-Yun Wang 2,  Weixin Zhang 1,  Zhenjian Zhuo 3,  Huiqin Guo 1,  Jiabin Liu 1,  Yue Zhuo 4,  Jue Tang 1,  Jing He 1,  Lei Miao 1
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China.
  • 2 Department of Pathology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, National Children's Medical Center for South Central Region, Guangzhou, Guangdong, China.
  • 3 Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
  • 4 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
PMID: 39902867 DOI: 10.1080/2162402X.2025.2460281
Abstract

The exploration of therapeutic targets in neuroblastoma (NB), which needs more attempts, can benefit patients with high-risk NB. Based on metabolomic and transcriptomic data in mediastinal NB tissues, we found that the content of long-chain acylcarnitine (LCAC) was increased and positively associated with Leptin expression in advanced NB. Leptin over-expression forced naïve CD4+ T cells to differentiate into Treg cells instead of Th17 cells, which benefited from NB cell proliferation, migration, and drug resistance. Mechanically, Leptin in NB cells blunted the activity of carnitine palmitoyltransferase 2 (CPT2), the key Enzyme for LCAC catabolism, by inhibiting Sirtuin 3-mediated CPT2 deacetylation, which depresses Oxidative Phosphorylation (OXPHOS) for energy supply and increases lactic acid (LA) production from glycolysis to modulate CD4+ T cell differentiation. These findings highlight that excess Leptin contributes to lipid metabolism dysfunction in NB cells and subsequently misdirects CD4+ T cell differentiation in tumor micro-environment (TME), indicating that targeting Leptin could be a therapeutic strategy for retarding NB progression.

Keywords

Neuroblastoma; T cell differentiation; leptin; long-chain fatty acid; tumor microenvironment.

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