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.
{"title":"Macrophage PD-1 regulates energy expenditure and metabolic dysfunction under immune checkpoint blockade","authors":"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","doi":"10.1016/j.cmet.2025.11.009","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.009","url":null,"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.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"148 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-05DOI: 10.1016/j.cmet.2025.11.007
Jian Gao, Wei Zhang, Qian Li, Dan Zhao, Jiayi Cai, Qing Wang, Xin Li, Tingting Liu, Jin Li, Wengan Xiao, Huimin Li, Min Du, Bing Zhang, Peiying Li, Hong Tu, Yu Gan
Caloric restriction (CR) induces tumor resistance in mammals, but its mechanisms remain poorly understood. Here, we found that CR altered the proportions and gene expression profiles of tumor-infiltrating neutrophils (TINs). Depletion of neutrophils largely abrogated CR-induced tumor inhibition across multiple murine cancer models, underscoring their critical role in CR’s broad anti-tumor effect. CR-induced gene expression changes in TINs were associated primarily with lipid-related processes, notably downregulating hypoxia-inducible lipid droplet-associated (HILPDA). This downregulation reduced lipid accumulation in TINs, limiting tumor growth and enhancing anti-tumor immunity by decreasing lipid transfer to tumor and immune effector cells. Upstream, CR reduced hypoxia-inducible factor 1 (HIF-1α) mRNA expression in circulating neutrophils by decreasing insulin-like growth factor 1 (IGF-1), thereby limiting HILPDA expression in TINs. Patients with lung cancer who had low baseline neutrophil HIF-1α mRNA exhibited improved responses to combined immunotherapy. These findings identify a novel neutrophil- and lipid-centered mechanism for CR-induced tumor inhibition, suggesting the IGF-1/HIF-1α/HILPDA axis as a therapeutic target.
{"title":"Restricting lipid accumulation in tumor-infiltrating neutrophils mediates caloric restriction-induced anti-cancer effects","authors":"Jian Gao, Wei Zhang, Qian Li, Dan Zhao, Jiayi Cai, Qing Wang, Xin Li, Tingting Liu, Jin Li, Wengan Xiao, Huimin Li, Min Du, Bing Zhang, Peiying Li, Hong Tu, Yu Gan","doi":"10.1016/j.cmet.2025.11.007","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.007","url":null,"abstract":"Caloric restriction (CR) induces tumor resistance in mammals, but its mechanisms remain poorly understood. Here, we found that CR altered the proportions and gene expression profiles of tumor-infiltrating neutrophils (TINs). Depletion of neutrophils largely abrogated CR-induced tumor inhibition across multiple murine cancer models, underscoring their critical role in CR’s broad anti-tumor effect. CR-induced gene expression changes in TINs were associated primarily with lipid-related processes, notably downregulating hypoxia-inducible lipid droplet-associated (HILPDA). This downregulation reduced lipid accumulation in TINs, limiting tumor growth and enhancing anti-tumor immunity by decreasing lipid transfer to tumor and immune effector cells. Upstream, CR reduced hypoxia-inducible factor 1 (HIF-1α) mRNA expression in circulating neutrophils by decreasing insulin-like growth factor 1 (IGF-1), thereby limiting HILPDA expression in TINs. Patients with lung cancer who had low baseline neutrophil HIF-1α mRNA exhibited improved responses to combined immunotherapy. These findings identify a novel neutrophil- and lipid-centered mechanism for CR-induced tumor inhibition, suggesting the IGF-1/HIF-1α/HILPDA axis as a therapeutic target.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"52 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.cmet.2025.11.001
Iyassu K. Sebhat, Monika J.M. Murphy, Shuqin Zheng, Robert J. Lovelett, Maja Engelstoft, Daniel Kosinski, Xiaodong Yang, Victoria Dunn, John Whang, Maximilian G. Lombardo, Adrian Heilbut, Giuseppe Terracina, Nicole Nicholas, Molly Leitner, Matthew J. Consolati, Bryan Chan, Gregory Poterewicz, Annemarie Vance, Jiajun Liu, Ann E. Weber, Shirly Pinto
A leading hypothesis for the effectiveness of bariatric surgery for weight loss is supraphysiologic activation of gut enteroendocrine cells (EECs), which results in elevated postprandial levels of satiety hormones, including glucagon-like peptide-1 (GLP-1). Here, we describe direct targeting of EECs to mimic effects of bariatric surgery. Advanced technologies were used to obtain a comprehensive understanding of EEC diversity, resulting in the identification of cells that express both satiety hormones and target receptors, including GPR40 (FFAR1) and GPR119. We developed gut-targeted agonists of these receptors, K-757 and K-833, and demonstrated synergistic hormone secretion in murine and human enteroids. The combination was efficacious in improving glucose tolerance and promoting weight loss in mice. The levels of circulating gut hormones observed in phase 1 trials exceeded levels observed in bariatric surgery, warranting further clinical investigation of these compounds for weight loss and glucose control.
{"title":"Gut enteroendocrine cell activation using a combination of GPR119 and GPR40 agonists results in synergistic hormone secretion in mice and humans","authors":"Iyassu K. Sebhat, Monika J.M. Murphy, Shuqin Zheng, Robert J. Lovelett, Maja Engelstoft, Daniel Kosinski, Xiaodong Yang, Victoria Dunn, John Whang, Maximilian G. Lombardo, Adrian Heilbut, Giuseppe Terracina, Nicole Nicholas, Molly Leitner, Matthew J. Consolati, Bryan Chan, Gregory Poterewicz, Annemarie Vance, Jiajun Liu, Ann E. Weber, Shirly Pinto","doi":"10.1016/j.cmet.2025.11.001","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.001","url":null,"abstract":"A leading hypothesis for the effectiveness of bariatric surgery for weight loss is supraphysiologic activation of gut enteroendocrine cells (EECs), which results in elevated postprandial levels of satiety hormones, including glucagon-like peptide-1 (GLP-1). Here, we describe direct targeting of EECs to mimic effects of bariatric surgery. Advanced technologies were used to obtain a comprehensive understanding of EEC diversity, resulting in the identification of cells that express both satiety hormones and target receptors, including GPR40 (FFAR1) and GPR119. We developed gut-targeted agonists of these receptors, K-757 and K-833, and demonstrated synergistic hormone secretion in murine and human enteroids. The combination was efficacious in improving glucose tolerance and promoting weight loss in mice. The levels of circulating gut hormones observed in phase 1 trials exceeded levels observed in bariatric surgery, warranting further clinical investigation of these compounds for weight loss and glucose control.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"18 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.cmet.2025.11.004
Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun
{"title":"Toward the next 20 years of Cell Metabolism","authors":"Salvatore Fabbiano, Mari-Carmen Fernández-Agüera, Beste Mutlu, Patrick Schaefer, Yongmei Sun","doi":"10.1016/j.cmet.2025.11.004","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.11.004","url":null,"abstract":"","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"159 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1016/j.cmet.2025.10.022
Baharan Meghdadi, Wajd N. Al-Holou, Andrew J. Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O’Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R. Qi, Vijay Tarnal, Sriram Venneti, C. Ryan Miller, Jann N. Sarkaria, Weihua Zhou, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R. Wahl, Deepak Nagrath
Recent advancements in metabolic flux estimations in vivo are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (13C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with 13C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance in vivo metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.
{"title":"Digital twins for in vivo metabolic flux estimations in patients with brain cancer","authors":"Baharan Meghdadi, Wajd N. Al-Holou, Andrew J. Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O’Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R. Qi, Vijay Tarnal, Sriram Venneti, C. Ryan Miller, Jann N. Sarkaria, Weihua Zhou, Theodore S. Lawrence, Costas A. Lyssiotis, Daniel R. Wahl, Deepak Nagrath","doi":"10.1016/j.cmet.2025.10.022","DOIUrl":"https://doi.org/10.1016/j.cmet.2025.10.022","url":null,"abstract":"Recent advancements in metabolic flux estimations <em>in vivo</em> are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (<sup>13</sup>C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with <sup>13</sup>C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance <em>in vivo</em> metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.","PeriodicalId":9840,"journal":{"name":"Cell metabolism","volume":"123 1","pages":""},"PeriodicalIF":29.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145651402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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