哈尔滨医科大学张志仁小组宣布他们探明了免疫检查点阻断下巨噬细胞PD-1调节能量消耗和代谢功能障碍。这一研究成果于2025年12月10日发表在国际顶尖学术期刊《细胞—代谢》上。

研究团队发现一种抗PD-1抗体靶向巨噬细胞PD-1，在不影响食物摄入的情况下减少能量消耗，增加小鼠对高脂肪饮食（HFD）诱导的肥胖和全身代谢紊乱的易感性。在哺乳动物雷帕霉素靶蛋白（mTOR）依赖的机制中，脂多糖（LPS）激活Unc -51样自噬激活激酶1 （ULK1）。活化的ULK1磷酸化PD-1 Thr250位点，通过破坏FBXO38-PD-1结合抑制FBXO38介导的PD-1泛素化和降解。磷酸化的PD-1与肌醇需要酶1α (IRE1α)相互作用，并减弱IRE1α的自磷酸化，从而抑制内质网（ER）应激介导的炎症反应。抑制IRE1α可通过挽救巨噬细胞特异性PD-1敲除小鼠减少的能量消耗来缓解HFD诱导的代谢紊乱。他们的发现强调了巨噬细胞PD-1在免疫检查点阻断、能量消耗和代谢功能障碍中的关键作用。巨噬细胞PD-1的兼职功能可能为对抗ICI治疗和HFD诱导的代谢疾病提供了新的理论基础。

研究人员表示，免疫检查点抑制剂（ICI）治疗增加代谢综合征的风险；潜在的机制仍然是未知的。

附：英文原文

Title: Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade

Author: Ming-Ming Wu, Yan-Chao Yang, Zhi-Qiang Hu, Jie-Yu Chang, Han Xiao, Chang Miao, Bo-Wen Zhang, Zhi-Xi He, Di Zhu, Yu-Ran Duan, Shuo Wang, Jian-Yu Liu, Zhan-Peng Guo, Yu Sun, Dan-Yang Liu, Miao Yu, Yue Zhang, Jian-Jun Mao, Shuai Jiang, Bing-Kun Zhang, Zhu Mei, Jun Gao, Chen Liang, Qiu-Shi Wang, Chang-Jiang Yu, Dan Zhao, Cheng-Hui Yan, Yue Li, Zhen-Wei Pan, Zheng Chen, Da-Qian Xu, Tong Liu, Yong Ji, Zhi-Ren Zhang

Issue&Volume: 2025-12-10

Abstract: Immune checkpoint inhibitor (ICI) therapies increase the risk of metabolic syndrome; the underlying mechanisms remain elusive. We show that an anti-PD-1 antibody targets macrophage PD-1 to reduce energy expenditure without affecting food intake, augmenting the susceptibility of mice to high-fat diet (HFD)-induced obesity and systemic metabolic disorders. Mechanistically, lipopolysaccharide (LPS) activates Unc-51-like autophagy activating kinase 1 (ULK1) in a mammalian target of rapamycin (mTOR)-dependent manner. Activated ULK1 phosphorylates PD-1 at Thr250 to inhibit FBXO38-mediated PD-1 ubiquitination and degradation by disrupting FBXO38-PD-1 binding. Phosphorylated PD-1 interacts with inositol-requiring enzyme 1α (IRE1α) and attenuates IRE1α autophosphorylation to suppress endoplasmic reticulum (ER) stress-mediated inflammatory responses. Suppressing IRE1α alleviates HFD-induced metabolic disorders in macrophage-specific PD-1 knockout mice by rescuing the reduced energy expenditure. Our findings highlight the critical role of macrophage PD-1 at the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction. The underscored moonlighting function of macrophage PD-1 may provide a new rationale for combating ICI therapy- and HFD-induced metabolic diseases.

DOI: 10.1016/j.cmet.2025.11.009

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00493-0