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

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2025-12-01 Epub Date: 2025-02-04 DOI:10.1080/2162402X.2025.2460281
Meng Li, Di Li, Hai-Yun Wang, Weixin Zhang, Zhenjian Zhuo, Huiqin Guo, Jiabin Liu, Yue Zhuo, Jue Tang, Jing He, Lei Miao
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引用次数: 0

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.

瘦素降低Th17/Treg比值,通过抑制肿瘤细胞长链脂肪酸分解代谢促进成神经细胞瘤的发生。
神经母细胞瘤(neuroblastoma, NB)治疗靶点的探索需要更多的尝试,可以使高危NB患者受益。基于纵隔NB组织的代谢组学和转录组学数据,我们发现,在晚期NB中,长链酰基肉碱(LCAC)的含量增加,并与瘦素的表达呈正相关。瘦素过表达迫使naïve CD4+ T细胞分化为Treg细胞而非Th17细胞,这有利于NB细胞的增殖、迁移和耐药。从机械上说,NB细胞中的瘦素通过抑制sirtuin 3介导的CPT2去乙酰化,减弱了LCAC分解代谢的关键酶——肉碱棕榈酰基转移酶2 (CPT2)的活性,CPT2去乙酰化抑制了氧化磷酸化(OXPHOS)的能量供应,增加了糖酵解产生的乳酸(LA),从而调节CD4+ T细胞分化。这些发现强调,过量的瘦素有助于NB细胞脂质代谢功能障碍,并随后在肿瘤微环境(TME)中误导CD4+ T细胞分化,表明靶向瘦素可能是一种延缓NB进展的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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