1
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Fang X, Ruan Y, Yin X, Wang J, Chen C, Hu Y, Wang H, Pi J, Xu Y. The role of SLC7A11 in arsenite-induced oncogenic phenotypes of human bronchial epithelial cells: A metabolic perspective. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 376:126381. [PMID: 40334737 DOI: 10.1016/j.envpol.2025.126381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 04/14/2025] [Accepted: 05/04/2025] [Indexed: 05/09/2025]
Abstract
Chronic arsenic exposure enhances the probability of lung cancer with the underlying mechanisms remain unknown. Glutamine-driven synthetic metabolism, including nucleotide synthesis, amino acid production, TCA cycle replenishment, glutathione synthesis, and lipid biosynthesis, is crucial for both cancer initiation and progression. This study demonstrated that chronic exposure to 0.1 μM arsenite for as long as 36 weeks induced malignant transformation in human bronchial epithelial cells (BEAS-2B). Metabolomics were used to systematically disclose metabolic characteristics in arsenic-transformed malignant (As-TM) cells. Significantly changed metabolites were enriched in alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, glutathione metabolism, butanoate metabolism, TCA cycle, and arginine and proline metabolism. It is worth noting that glutamate located at the intersection of the enriched metabolism pathways. Glutamine deprivation attenuated the oncogenic phenotypes, including capacity of wound healing and proliferation, in As-TM cells. And the expression levels of mRNA and proteins associated with glutamine metabolism-related transporters and enzymes, including SLC7A11, GCLM, and GCLC, were significantly increased, with SLC7A11 exhibiting the most substantial increase. Moreover, arsenite transformation progressively elevated SLC7A11 mRNA and protein levels over time. The SLC7A11 inhibitor sulfasalazine remarkably attenuated arsenite-induced oncogenic phenotypes. Collectively, our data suggest that chronic arsenite exposure enhances glutamine metabolism through upregulation of SLC7A11, thereby promoting cell proliferation and malignant transformation. These results provide new insights for preventive and therapeutic strategies for lung cancer linked to arsenic exposure.
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Affiliation(s)
- Xin Fang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Yihui Ruan
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Xianhang Yin
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Junyi Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Chen Chen
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Yuxin Hu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China
| | - Huihui Wang
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang, Liaoning, 110122, China
| | - Jingbo Pi
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang, Liaoning, 110122, China
| | - Yuanyuan Xu
- Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, 110122, China; School of Public Health, China Medical University, Shenyang, Liaoning, 110122, China; Key Laboratory of Liaoning Province on Toxic and Biological Effects of Arsenic, China Medical University, Shenyang, Liaoning, 110122, China.
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2
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Wang H, Xu F, Wang C. Metabolic reprogramming of tumor microenviroment by engineered bacteria. Semin Cancer Biol 2025; 112:58-70. [PMID: 40157514 DOI: 10.1016/j.semcancer.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/16/2025] [Accepted: 03/21/2025] [Indexed: 04/01/2025]
Abstract
The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.
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Affiliation(s)
- Heng Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Fang Xu
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China
| | - Chao Wang
- Laboratory for Biomaterial and Immunoengineering, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
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3
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Plata-Gómez AB, Ho PC. Age- and diet-instructed metabolic rewiring of the tumor-immune microenvironment. J Exp Med 2025; 222:e20241102. [PMID: 40214641 PMCID: PMC11987706 DOI: 10.1084/jem.20241102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.
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Affiliation(s)
- Ana Belén Plata-Gómez
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
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4
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Fabiano ED, Poole JM, Reinhart-King CA. Mechanometabolism: recent findings on the intersection of cell adhesion, cell migration, and metabolism. Am J Physiol Cell Physiol 2025; 328:C1866-C1879. [PMID: 40271988 DOI: 10.1152/ajpcell.00892.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 11/26/2024] [Accepted: 04/21/2025] [Indexed: 04/25/2025]
Abstract
Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely, how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.
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Affiliation(s)
- Emily D Fabiano
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
- Department of Bioengineering, Rice University, Houston, Texas, United States
| | - Jenna M Poole
- Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama, United States
| | - Cynthia A Reinhart-King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
- Department of Bioengineering, Rice University, Houston, Texas, United States
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5
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Zhu Y, Lin X, Wang T, Wang S, Wang W, Ke M, Zhu Y, Zhang B, Ofosuhemaa P, Wang Y, Hu M, Yang W, Hu A, Huang F, Zhao Q. Associated effects of blood metal(loid) exposure and impaired glucose metabolism in patients with gastric precancerous lesions or gastric cancer. Biometals 2025; 38:887-902. [PMID: 40232351 DOI: 10.1007/s10534-025-00684-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 04/04/2025] [Indexed: 04/16/2025]
Abstract
Exposure to metal(loid)s and glucose metabolism may influence the progression of gastric precancerous lesions (GPLs) or gastric cancer (GC), but their combined effects remain unclear. Our study aimed to elucidate the combined impact of metal (including metalloid and trace element) exposure and disturbances in glucose metabolism on the progression of GPLs and GC. From a prospective observational cohort of 1829 individuals, their metal(loid) levels and blood metabolism were analysed via inductively coupled plasma‒mass spectrometry and targeted metabolomics gas chromatography‒mass spectrometry, respectively. From healthy normal controls (NC) or GPLs to GC, we observed that the aluminum and arsenic levels decreased, whereas the vanadium, titanium and rubidium levels increased, but the iron, copper, zinc and barium levels initially decreased but then increased; these changes were not obvious from the NC to GPL group. With respect to glucose homeostasis, most metabolites decreased, except for phosphoenolpyruvate (PEP), which increased. Multiple logistic regression analysis revealed that titanium and phosphoenolpyruvate might be risk factors for GPLs, that barium is a protective factor for GC, and that D-glucaric acid might be a protective factor for GPLs and GC. Selenium, vanadium, titanium, succinate, maleate, isocitrate, PEP, and the tricarboxylic acid cycle (TCA) had good predictive potential for GPL and GC. Additionally, metal(loid)s such as arsenic, titanium, barium, aluminum, and vanadium were significantly correlated with multiple glucose metabolites involved in the TCA cycle in the GPL and GC groups. Our findings imply that metal(loid) exposure disrupts glucose metabolism, jointly influencing GPL and GC progression.
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Affiliation(s)
- Yuting Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Xiao Lin
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
- Department of Tuberculosis Control, Xiangcheng Center for Disease Control and Prevention, Suzhou, 215131, China
| | - Tingting Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
- Department of Hospital Nosocomial Infection, Chaohu Hospital of Anhui Medical University, Hefei, 230032, China
| | - Sheng Wang
- Research and Experiment Center, Anhui Medical University, Hefei, 230032, China
| | - Wuqi Wang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Mengran Ke
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Yan Zhu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Bowen Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Princess Ofosuhemaa
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Yalei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230011, China
| | - Mingjun Hu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Wanshui Yang
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Anla Hu
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China
| | - Fen Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230032, China.
| | - Qihong Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, China.
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6
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Si Z, Tian L, Zhou H, Lin J, Zhou J. In Vivo Interrogation of Cell-Penetrating Peptide Function: Accumulation in Tumors and the Potential as a Specific PET Probe. Bioconjug Chem 2025; 36:1088-1097. [PMID: 40202497 PMCID: PMC12101444 DOI: 10.1021/acs.bioconjchem.5c00128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 03/28/2025] [Accepted: 03/31/2025] [Indexed: 04/10/2025]
Abstract
We aimed to evaluate the biodistribution and specificity of 68Ga-DOTA-TAT and RHO-TAT using MGC-803 and HT-29 tumor cells as well as tumor-xenografted nude mice and to demonstrate its application in positron emission tomography (PET) imaging. The in vitro evaluation of 68Ga-DOTA-TAT was assessed in MGC-803 and HT-29 cell lines, and the in vivo evaluation of 68Ga-DOTA-TAT was also performed in mice bearing MGC-803 or HT-29 tumors, respectively. Fluorescence microscopy was also employed to evaluate the specificity of RHO-TAT in vitro in MGC-803 and HT-29 cells as well as ex vivo in tumor slices of the corresponding tumor models. The in vivo imaging differences between 68Ga-DOTA-TAT and 18F-FDG in MGC-803 and HT-29 tumors were also studied. The biodistribution and micro-PET results demonstrated significant uptake of 68Ga-DOTA-TAT in non-FDG-avid MGC-803 tumors, whereas there was negligible uptake in FDG-avid HT-29 tumors. RHO-TAT showed superior fluorescence microscopy imaging effects in MGC-803 cells and tumor slices but not in HT-29 cells and tumor slices, which were consistent with the in vivo results. 68Ga-DOTA-TAT combined with 18F-FDG can be applied noninvasively in cancers with PET imaging for potential patient selection and stratification. We demonstrated a higher binding of 68Ga-DOTA-TAT and RHO-TAT to MGC-803 cells as well as to non-FDG-avid MGC-803 xenografted tumors and a lower binding to HT-29 cells and FDG-avid xenografted tumors. These results suggest that TAT has the potential to be a ligand for targeting certain tumors.
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Affiliation(s)
- Zhan Si
- Department
of Nuclear Medicine, Zhongshan Hospital,
Fudan University, Shanghai200032, China
- Institute
of Nuclear Medicine, Fudan University, Shanghai200032, China
| | - Lulu Tian
- Department
of Pharmacy, Tongji Hospital, School of Medicine, Tongji University, Shanghai200065, China
| | - Hongxin Zhou
- Liver
Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis
and Cancer Invasion, Ministry of Education, Fudan University, Shanghai200032, China
| | - Jiasheng Lin
- Department
of Nuclear Medicine, Shanghai Xuhui Central Hospital, Fudan University, Shanghai200237, China
| | - Jun Zhou
- Department
of Nuclear Medicine, Shanghai Xuhui Central Hospital, Fudan University, Shanghai200237, China
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7
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Aviles-Huerta D, Del Pizzo R, Kowar A, Baig AH, Palazzo G, Stepanova E, Amaya Ramirez CC, D'Agostino S, Ratto E, Pechincha C, Siefert N, Engel H, Du S, Cadenas-De Miguel S, Miao B, Cruz-Vilchez VM, Müller-Decker K, Elia I, Sun C, Palm W, Loayza-Puch F. Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in the tumor microenvironment. Nat Commun 2025; 16:4652. [PMID: 40389477 PMCID: PMC12089342 DOI: 10.1038/s41467-025-59986-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 05/09/2025] [Indexed: 05/21/2025] Open
Abstract
The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.
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Affiliation(s)
- Daniela Aviles-Huerta
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Rossella Del Pizzo
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Alexander Kowar
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Ali Hyder Baig
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Giuliana Palazzo
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
| | - Ekaterina Stepanova
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Cinthia Claudia Amaya Ramirez
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Sara D'Agostino
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Edoardo Ratto
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
- Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Catarina Pechincha
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
- Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Nora Siefert
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
- Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Helena Engel
- Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany
- Immune Regulation in Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Shangce Du
- Immune Regulation in Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, Heidelberg, Germany
| | | | - Beiping Miao
- Immune Regulation in Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Victor M Cruz-Vilchez
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Karin Müller-Decker
- Core Facility Tumor Models, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Ilaria Elia
- Department of Cellular and Molecular Medicine, KU Leuven, 3000, Leuven, Belgium
| | - Chong Sun
- Immune Regulation in Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Wilhelm Palm
- Division of Cell Signaling and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Fabricio Loayza-Puch
- Translational Control and Metabolism, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
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8
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Yang X, Deng Y, Ye Y, Meng J, Su M, Wei W, Qin Y, Zhang H, Tian Y, Deng S, Liao Z, Zhou Z, Li J, Hu Y, Zhang B, Sun Y, Wen L, Zhang Z, Huang F, Wan C, Yang K. Macrophage-Derived Itaconate Suppresses Dendritic Cell Function to Promote Acquired Resistance to Anti-PD-1 Immunotherapy. Cancer Res 2025; 85:1842-1856. [PMID: 40036156 DOI: 10.1158/0008-5472.can-24-2982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 01/07/2025] [Accepted: 02/26/2025] [Indexed: 03/06/2025]
Abstract
Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy. Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.
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Affiliation(s)
- Xiao Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Yue Deng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Ying Ye
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Jingshu Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Mengyao Su
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Wenwen Wei
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Haibo Zhang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China
| | - Yu Tian
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Suke Deng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Zhiyun Liao
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Zhiyuan Zhou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Jie Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Yan Hu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Bin Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Yajie Sun
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Lu Wen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Zhanjie Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Fang Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Chao Wan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
| | - Kunyu Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China
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9
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Bi Q, Zhao J, Nie J, Huang F. Metabolic pathway analysis of tumors using stable isotopes. Semin Cancer Biol 2025; 113:9-24. [PMID: 40348000 DOI: 10.1016/j.semcancer.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 04/14/2025] [Accepted: 05/05/2025] [Indexed: 05/14/2025]
Abstract
Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.
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Affiliation(s)
- Qiufen Bi
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China
| | - Junzhang Zhao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510655, China
| | - Jun Nie
- Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Fang Huang
- Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan 430022, China.
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10
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Karimova AF, Khalitova AR, Suezov R, Markov N, Mukhamedshina Y, Rizvanov AA, Huber M, Simon HU, Brichkina A. Immunometabolism of tumor-associated macrophages: A therapeutic perspective. Eur J Cancer 2025; 220:115332. [PMID: 40048925 DOI: 10.1016/j.ejca.2025.115332] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/22/2025] [Accepted: 02/25/2025] [Indexed: 04/26/2025]
Abstract
Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.
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Affiliation(s)
- Adelya F Karimova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Adelya R Khalitova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Roman Suezov
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany
| | - Nikita Markov
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Yana Mukhamedshina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Albert A Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia; Division of Medical and Biological Sciences, Tatarstan Academy of Sciences, Kazan, Russia
| | - Magdalena Huber
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany
| | - Hans-Uwe Simon
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia; Institute of Pharmacology, University of Bern, Bern, Switzerland; Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Anna Brichkina
- Institute of Systems Immunology, Center for Tumor and Immune Biology, Philipps University of Marburg, Marburg, Germany.
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11
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Wang J, Gao X, Ren J, Song B, Zhang W, Yuan J. A novel ratiometric luminescent probe based on a ruthenium(II) complex-rhodamine scaffold for ATP detection in cancer cells. Talanta 2025; 286:127538. [PMID: 39778491 DOI: 10.1016/j.talanta.2025.127538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/30/2024] [Accepted: 01/03/2025] [Indexed: 01/11/2025]
Abstract
Adenosine 5'-triphosphate (ATP) plays a pivotal role as an essential intermediate in energy metabolism, influencing nearly all biological metabolic processes. Cancer cells predominantly rely on glycolysis for ATP production, differing significantly from normal cells. Real-time in situ monitoring and rapid response to intracellular ATP levels offers more valuable insights into cancer cell physiology. Herein, we report a novel ratiometric luminescent probe, Ru-Rho, comprised of a ruthenium(II)-based complex and rhodamine 6G (Rho 6G) with excellent water solubility and photostability. Notably, Ru-Rho selectively responds to ATP at acidic conditions, matching the need of monitoring ATP under the acidic intracellular environment of cancer cells. Moreover, the fast ratiometric detection and imaging of ATP under single wavelength excitation improve the detection accuracy. Ru-Rho has been effectively utilized not only for ratio imaging ATP in cells and zebrafish, but also for assessing the efficacy of glycolysis-inhibiting anticancer drugs in intracellular levels, which accelerates the screening process for anticancer drugs and supports the development of new therapeutic agents. The design strategy based on transition metal ruthenium(II) complexes opens a new pathway for constructing ATP luminescent probes, allowing for better adaptation to complex detection requirements.
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Affiliation(s)
- Jiacheng Wang
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
| | - Xiaona Gao
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
| | - Junyu Ren
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
| | - Bo Song
- School of Chemistry, Dalian University of Technology, Dalian 116024, China
| | - Wenzhu Zhang
- School of Chemistry, Dalian University of Technology, Dalian 116024, China.
| | - Jingli Yuan
- College of Life Science, Dalian Minzu University, Dalian 116600, China.
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12
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Liu W, Hu X, Bao Z, Li Y, Zhang J, Yang S, Huang Y, Wang R, Wu J, Xu X, Sang Q, Di W, Lu H, Yin X, Qian K. Serum metabolic fingerprints encode functional biomarkers for ovarian cancer diagnosis: a large-scale cohort study. EBioMedicine 2025; 115:105706. [PMID: 40273469 PMCID: PMC12051638 DOI: 10.1016/j.ebiom.2025.105706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 03/27/2025] [Accepted: 04/02/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Ovarian cancer (OC) ranks as the most lethal gynaecological malignancy worldwide, with early diagnosis being crucial yet challenging. Current diagnostic methods like transvaginal ultrasound and blood biomarkers show limited sensitivity/specificity. This study aimed to identify and validate serum metabolic biomarkers for OC diagnosis using the largest cohort reported to date. METHODS We constructed a large-scale OC-associated cohort of 1432 subjects, including 662 OC, 563 benign ovarian disease, and 207 healthy control subjects, across retrospective (n = 1073) and set-aside validation (n = 359) cohorts. Serum metabolic fingerprints (SMFs) were recorded using nanoparticle-enhanced laser desorption/ionization mass spectrometry (NELDI-MS). A diagnostic panel was developed through machine learning of SMFs in the discovery cohort and validated in independent verification and set-aside validation cohorts. The identified metabolic biomarkers were further validated using liquid chromatography MS and their biological functions were assessed in OC cell lines. FINDINGS We identified a metabolic biomarker panel including glucose, histidine, pyrrole-2-carboxylic acid, and dihydrothymine. This panel achieved consistent areas under the curve (AUCs) of 0.87-0.89 for distinguishing between malignant and benign ovarian masses across all cohorts, and improved to AUCs of 0.95-0.99 when combined with risk of ovarian malignancy algorithm (ROMA). In vitro validation provided initial biological context for the metabolic alterations observed in our diagnostic panel. INTERPRETATION Our study established a reliable serum metabolic biomarker panel for OC diagnosis with potential clinical translations. The NELDI-MS based approach offers advantages of fast analytical speed (∼30 s/sample) and low cost (∼2-3 dollars/sample), making it suitable for large-scale clinical applications. FUNDING MOST (2021YFA0910100), NSFC (82421001, 823B2050, 824B2059, and 82173077), Medical-Engineering Joint Funds of Shanghai Jiao Tong University (YG2021GD02, YG2024ZD07, and YG2023ZD08), Shanghai Science and Technology Committee Project (23JC1403000), Shanghai Institutions of Higher Learning (2021-01-07-00-02-E00083), Shanghai Jiao Tong University Inner Mongolia Research Institute (2022XYJG0001-01-16), Sichuan Provincial Department of Science and Technology (2024YFHZ0176), Innovation Research Plan by the Shanghai Municipal Education Commission (ZXWF082101), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20210700), Basic-Clinical Collaborative Innovation Project from Shanghai Immune Therapy Institute, Guangdong Basic and Applied Basic Research Foundation (2024A1515013255).
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Affiliation(s)
- Wanshan Liu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Xiaoxiao Hu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China
| | - Zhouzhou Bao
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China
| | - Yanyan Li
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Juxiang Zhang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Shouzhi Yang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Yida Huang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Ruimin Wang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Jiao Wu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Xiaoyu Xu
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Qi Sang
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China
| | - Wen Di
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
| | - Huaiwu Lu
- Department of Gynecologic Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, PR China.
| | - Xia Yin
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China.
| | - Kun Qian
- Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China; State Key Laboratory for Oncogenes and Related Genes, Shanghai Key Laboratory of Gynecologic Oncology, Shanghai 200127, PR China; State Key Laboratory of Systems Medicine for Cancer, School of Biomedical Engineering, Institute of Medical Robotics and Shanghai Academy of Experimental Medicine, Shanghai Jiao Tong University, Shanghai 200030, PR China; Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, PR China.
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13
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Wang Y, Wilfahrt D, Jonker P, Lontos K, Cai C, Cameron B, Xie B, Peralta RM, Schoedel ER, Gunn WG, AminiTabrizi R, Shah H, Rivadeneira DB, Muir A, Delgoffe GM. Tumour interstitial fluid-enriched phosphoethanolamine suppresses T cell function. Nat Cell Biol 2025; 27:835-846. [PMID: 40258951 DOI: 10.1038/s41556-025-01650-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 03/04/2025] [Indexed: 04/23/2025]
Abstract
Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.
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Affiliation(s)
| | - Drew Wilfahrt
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Patrick Jonker
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | | | - Chufan Cai
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
| | - Benjamin Cameron
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Bingxian Xie
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Ronal M Peralta
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | | | - William G Gunn
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Roya AminiTabrizi
- Metabolomics Platform, Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA
| | - Hardik Shah
- Metabolomics Platform, Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA
| | - Dayana B Rivadeneira
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA
| | - Alexander Muir
- Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
| | - Greg M Delgoffe
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
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14
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Chen J, Wang S, Ding Y, Xu D, Zheng S. Radiotherapy-induced alterations in tumor microenvironment: metabolism and immunity. Front Cell Dev Biol 2025; 13:1568634. [PMID: 40356601 PMCID: PMC12066526 DOI: 10.3389/fcell.2025.1568634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.
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Affiliation(s)
- Jinpeng Chen
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Sheng Wang
- Department of Radiation Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu, China
| | - Yue Ding
- Department of General Surgery, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
- Southeast University Medical School, Nanjing, Jiangsu, China
| | - Duo Xu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shiya Zheng
- Southeast University Medical School, Nanjing, Jiangsu, China
- Department of Oncology, Southeast University, Zhongda Hospital Southeast University, Nanjing, Jiangsu, China
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15
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Liu L, Zhang S, Ren Y, Wang R, Zhang Y, Weng S, Zhou Z, Luo P, Cheng Q, Xu H, Ba Y, Zuo A, Liu S, Liu Z, Han X. Macrophage-derived exosomes in cancer: a double-edged sword with therapeutic potential. J Nanobiotechnology 2025; 23:319. [PMID: 40287762 PMCID: PMC12034189 DOI: 10.1186/s12951-025-03321-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 03/11/2025] [Indexed: 04/29/2025] Open
Abstract
Solid cancer contains a complicated communication network between cancer cells and components in the tumor microenvironment (TME), significantly influencing the progression of cancer. Exosomes function as key carriers of signaling molecules in these communications, including the intricate signalings of tumor-associated macrophages (TAMs) on cancer cells and the TME. With their natural lipid bilayer structures and biological activity that relates to their original cell, exosomes have emerged as efficient carriers in studies on cancer therapy. Intrigued by the heterogeneity and plasticity of both macrophages and exosomes, we regard macrophage-derived exosomes in cancer as a double-edged sword. For instance, TAM-derived exosomes, educated by the TME, can promote resistance to cancer therapies, while macrophage-derived exosomes generated in vitro have shown favorable potential in cancer therapy. Here, we depict the reasons for the heterogeneity of TAM-derived exosomes, as well as the manifold roles of TAM-derived exosomes in cancer progression, metastasis, and resistance to cancer therapy. In particular, we emphasize the recent advancements of modified macrophage-derived exosomes in diverse cancer therapies, arguing that these modified exosomes are endowed with unique advantages by their macrophage origin. We outline the challenges in translating these scientific discoveries into clinical cancer therapy, aiming to provide patients with safe and effective treatments.
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Affiliation(s)
- Long Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Siying Zhang
- Medical School of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuqing Ren
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ruizhi Wang
- Medical School of Zhengzhou University, Zhengzhou, Henan, China
| | - Yuyuan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Siyuan Weng
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Peng Luo
- The Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hui Xu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yuhao Ba
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Anning Zuo
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Shutong Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Zaoqu Liu
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Interventional Institute of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, 450052, Henan, China.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Xinwei Han
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Interventional Institute of Zhengzhou University, Zhengzhou, 450052, Henan, China.
- Interventional Treatment and Clinical Research Center of Henan Province, Zhengzhou, 450052, Henan, China.
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16
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Hui W, Lei KM, Liu Y, Huang X, Zhong Y, Chen X, Wei M, Yan J, Shen R, Mak PI, Martins RP, Yi S, Wang P, Jia Y. Identification and Drug Screening of Single Cells from Human Tumors on Semiconductor Chip for Cancer Precision Medicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2503131. [PMID: 40271835 DOI: 10.1002/advs.202503131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/02/2025] [Indexed: 04/25/2025]
Abstract
Drug screening of primary tumor cells directly assesses the drug efficacy on specific tumors, promoting personalized cancer treatment. The application of a microfluidic platform has realized drug screening using a limited amount of biopsy samples for cancer precision medicine. However, all the techniques face an inevitable issue of not all the primary tumor cells being cancer cells. Here, a system is introduced that integrates single-cell identification and drug screening on one semiconductor chip so that both drug efficacy on cancer cells and drug toxicity on noncancerous cells can be obtained simultaneously. An integrated circuit is built on the semiconductor chip for single-cell electric impedance sensing (IC-ECIS) of ultra-weak signals for distinguishing cancer cells from noncancerous cells without affecting cell vitality. Single-cell identification is validated using breast, lung, and liver cell lines as well as liver cancer specimens from clinical patients. The accuracy on commercial cell lines is ≈80%, and the diagnostic results of tumor tissues are consistent with clinical pathology results. Drug screening is run on the same chip after single cell identification for dual evaluation of drug efficacy and toxicity in both breast cancer models and clinical liver cancer patients. The on-chip drug screening is confirmed with off-chip counterpart experiments in breast cell lines. The effectiveness or ineffectiveness of a drug screened on the IC-ECIS chip demonstrated consistency in the presence or absence of specific mutations in the drug-related genes determined via exome sequencing of individual liver tumors, validating the method for precision medicine.
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Affiliation(s)
- Wenhao Hui
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Ka-Meng Lei
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Yingying Liu
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Xinru Huang
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China
| | - Yunlong Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China
| | - Xiaojun Chen
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Lingnan Normal University, Zhanjiang, 524000, China
| | - Mingji Wei
- Electrical and Information Engineering, Jiangsu University, Zhenjiang, 212000, China
| | - Jie Yan
- Department of Physics, National University of Singapore, Singapore, 546080, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, 546080, Singapore
| | - Ren Shen
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Pui-In Mak
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Rui P Martins
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
- On leave from Instituto Superior Tecnico, Universidade de Lisboa, Lisboa, 1649-004, Portugal
| | - Shuhong Yi
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China
| | - Yanwei Jia
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, 999078, Macau
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Hung JT, Mynam RS, Patel MA, Ozogbo S, LoConte NK, Kratz JD. Immune-Based Therapies in Pancreatic Cancer: a Systematic Review of Ongoing Clinical Trials (2020-2022). J Gastrointest Cancer 2025; 56:103. [PMID: 40259076 DOI: 10.1007/s12029-025-01194-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/09/2025] [Indexed: 04/23/2025]
Abstract
INTRODUCTION Immune-based treatment strategies have emerged across solid organ malignancies largely with the development of immune checkpoint inhibitors. To date, these strategies have not improved clinical outcomes in pancreatic ductal adenocarcinoma (PDAC). METHODS Here, we perform a systematic review to summarize available evidence for recent immune-based treatment strategies in PDAC. We analyze trends in activated clinical trials queried from clinicaltrials.gov in the years 2020-2022. We review study design, sponsorship, and trends in the phase of development. There is a growing emergence of multiple new classes of immune-based targets and combination strategies in early-phase development. RESULTS Immune-based clinical trials in PDAC are highly collaborative including primarily stakeholders in government, industry, and academic medical centers. In this period, a majority of trials have integrated a non-randomized design (83.2%), including a trend towards an increase in Phase I/II clinical trials. This analysis found a growing list of studies using combinations including inhibitors of vascular endothelial growth factors (VEGF), an expanded set of vaccine-based strategies, and the use of Bispecific T-Cell Engagers (BiTEs). Immune checkpoint inhibitors have been a mainstay of combination strategies including the use of new immune checkpoint inhibitors (CD40, TIGIT). CONCLUSION Immune-based strategies in PDAC have expanded across new targets and the complexities of combinatory approaches. Integrating this work across key stakeholders remains of critical importance to improve clinical outcomes.
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Affiliation(s)
- Justine T Hung
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Ritwick S Mynam
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Monica A Patel
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Stanley Ozogbo
- Department of Internal Medicine, St Elizabeth Hospital, Youngstown, OH, USA
| | - Noelle K LoConte
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA
| | - Jeremy D Kratz
- Division of Hematology, Medical Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
- University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
- William S. Middleton Veterans Administration Health System, Madison, WI, USA.
- Center for Human Genomics and Precision Medicine, University of Wisconsin, 1111 Highland Ave, 2784 West Wedge, MadisonWI, WI, 53705, USA.
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Zhang L, Chen L, Deng Y, Chen H, Wu Y, An P, Fan J, Jiang D, Lan X, Cao W. Elevated 18F-FDG accumulation in a malignant epithelioid angiomyolipoma: a case report and review of literature. Front Oncol 2025; 15:1555092. [PMID: 40308494 PMCID: PMC12040656 DOI: 10.3389/fonc.2025.1555092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025] Open
Abstract
Epithelioid angiomyolipoma (EAML) is a tumor with malignant potential, as evidenced by its pathological features. Further investigation into its additional characteristics, particularly in imaging, is of great significance for non-invasive detection methods to understand its malignant potential. In this context, we present a case study of a 47-year-old male patient with a right renal EAML. The patient underwent nephrectomy but subsequently developed liver metastasis. Next-generation sequencing confirmed mutations of tuberous sclerosis 2 (TSC2) in both the primary and metastatic lesions. Consequently, the patient received maintenance treatment with the mTOR inhibitor, everolimus. However, treatment was discontinued after six months due to disease progression. Subsequent 18F-FDG PET/CT imaging revealed a large heterogeneous hypermetabolic mass in the liver, along with two other hypermetabolic metastases near the liver capsule. The patient's prognosis was poor, with indicators such as TSC2 mutation, tumor necrosis, high Ki-67 expression, and α-SMA-negative fibroblasts. Despite reoperation, the patient still succumbed to disease progression. The occurrence of malignant metastatic EAML detected using 18F-FDG PET/CT imaging is infrequent. We conducted a comprehensive review of the relevant literature on 18F-FDG PET/CT imaging for EAML. Notably, this article emphasizes that elevated 18F-FDG uptake in EAML may serve as a novel indicator of malignant EAML.
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Affiliation(s)
- Li Zhang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Leqing Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yinqian Deng
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Huanyu Chen
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yujun Wu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Peng An
- Department of Radiology, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dawei Jiang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Wei Cao
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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19
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Zhang M, Zheng H, Zhu X, Liu S, Jin H, Chen Y, Wan L, Zhang S, Zhang H. Synchronously Evoking Disulfidptosis and Ferroptosis via Systematical Glucose Deprivation Targeting SLC7A11/GSH/GPX4 Antioxidant Axis. ACS NANO 2025; 19:14233-14248. [PMID: 40178511 DOI: 10.1021/acsnano.5c00730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Disulfidptosis and ferroptosis are recently identified programmed cell deaths for tumor therapy, both of which highly depend on the intracellular cystine/cysteine transformation on the cystine transporter solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis. However, disulfidptosis and ferroptosis are usually asynchronous due to the opposite effect of cystine transport on them. Herein, systematic glucose deprivation, by both inhibiting upstream glucose uptake and promoting downstream glucose consumption, is proposed to synchronously evoke disulfidptosis and ferroptosis. As an example, Au nanodots and Fe-apigenin (Ap) complexes coloaded FeOOH nanoshuttles (FeOOH@Fe-Ap@Au NSs) are employed to regulate the SLC7A11/GSH/GPX4 axis for performing disulfidptosis- and ferroptosis-mediated tumor therapy synchronously. In this scenario, Au nanodots exhibit glucose oxidase-like activity when consuming massive glucose. Meanwhile, Ap can inhibit glucose uptake by downregulating glucose transporter 1, depriving glucose fundamentally. The systematical glucose deprivation limits the supplement of NADPH and suppresses cystine/cysteine transformation on the SLC7A11/GSH/GPX4 axis, thus solving the contradiction of cystine transport on disulfidptosis and ferroptosis. In addition, the efficient delivery of exogenous iron ions by FeOOH@Fe-Ap@Au NSs and self-supplied H2O2 through Au nanodots-catalytic glucose oxidation facilitate intracellular Fenton reaction and therewith help to amplify ferroptosis. As a result of synchronous occurrence of disulfidptosis and ferroptosis, FeOOH@Fe-Ap@Au NSs exhibit good efficacy in an ovarian cancer therapeutic model.
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Affiliation(s)
- Mengsi Zhang
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, P. R. China
- Department of Gynecological Oncology, Gynecology and Obstetrics Center, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Hao Zheng
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Xuanqi Zhu
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Shuwei Liu
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Hao Jin
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Yang Chen
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
| | - Lanlan Wan
- Department of Anesthesia, The Second Hospital of Jilin University, Changchun 130041, P. R. China
| | - Songling Zhang
- Department of Gynecological Oncology, Gynecology and Obstetrics Center, The First Hospital of Jilin University, Changchun 130021, P. R. China
| | - Hao Zhang
- Joint Laboratory of Opto-Functional Theranostics in Medicine and Chemistry, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130021, P. R. China
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P. R. China
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20
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Ciombor KK, Bae SW, Whisenant JG, Ayers GD, Sheng Q, Peterson TE, Smith GT, Lin K, Chowdhury S, Kanikarla Marie P, Sorokin A, Cohen AS, Goff LW, Cardin DB, Shen JP, Kopetz S, Eng C, Shyr Y, Berlin J, Manning HC. Results of the Phase I/II Study and Preliminary B-cell Gene Signature of Combined Inhibition of Glutamine Metabolism and EGFR in Colorectal Cancer. Clin Cancer Res 2025; 31:1437-1448. [PMID: 39927885 PMCID: PMC11996605 DOI: 10.1158/1078-0432.ccr-24-3133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 11/20/2024] [Accepted: 02/06/2025] [Indexed: 02/11/2025]
Abstract
PURPOSE EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression. PATIENTS AND METHODS We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET as potential treatment response biomarkers. RESULTS The combination of panitumumab and CB-839 was tolerable with manageable side effects, including grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response, and five had stable disease, with a 41% disease control rate. Median progression-free survival and overall survival were 1.84 and 8.87 months, respectively. A positive correlation between "B-score" and lesion size reduction suggested its association with clinical benefit (partial response and stable disease). Lower "B-score" correlated with greater tumor avidity for glutamine by PET, indicating B-cell activation sensitivity to glutamine depletion. CONCLUSIONS The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B-cell activation signature "B-score" emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.
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Affiliation(s)
- Kristen K Ciombor
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Seong-Woo Bae
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer G Whisenant
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Gregory D Ayers
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Quanhu Sheng
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Todd E Peterson
- Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Gary T Smith
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kangyu Lin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Saikat Chowdhury
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Preeti Kanikarla Marie
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Allison S Cohen
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri
| | - Laura W Goff
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Dana B Cardin
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Cathy Eng
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jordan Berlin
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - H Charles Manning
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas
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21
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Wang X, Wang Z, Liu Z, Huang F, Pan Z, Zhang Z, Liu T. Nutritional strategies in oncology: The role of dietary patterns in modulating tumor progression and treatment response. Biochim Biophys Acta Rev Cancer 2025; 1880:189322. [PMID: 40228747 DOI: 10.1016/j.bbcan.2025.189322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/08/2025] [Accepted: 04/10/2025] [Indexed: 04/16/2025]
Abstract
Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.
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Affiliation(s)
- Xueying Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zeyao Wang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zihan Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Fanxuan Huang
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China
| | - Zhaoyu Pan
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Hunan, China
| | - Zhiren Zhang
- Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China; Departments of Cardiology and Pharmacy and Breast Cancer surgery, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Heilongjiang Key Laboratory for Metabolic Disorder and Cancer Related Cardiovascular Diseases, Harbin, China.
| | - Tong Liu
- Department of Oncological Surgery, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China; Departments of Cardiology and Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, NHC Key Laboratory of Cell Transplantation, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
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22
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Qiu X, Gao Q, Wang J, Zhang Z, Tao L. The microbiota-m 6A-metabolism axis: Implications for therapeutic strategies in gastrointestinal cancers. Biochim Biophys Acta Rev Cancer 2025; 1880:189317. [PMID: 40222422 DOI: 10.1016/j.bbcan.2025.189317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 04/06/2025] [Accepted: 04/06/2025] [Indexed: 04/15/2025]
Abstract
Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, with metabolic reprogramming recognized as a central driver of tumor progression and therapeutic resistance. Among the key regulatory layers, N6-methyladenosine (m6A) RNA modification-mediated by methyltransferases (writers such as METTL3/14), RNA-binding proteins (readers like YTHDFs and IGF2BPs), and demethylases (erasers including FTO and ALKBH5), plays a pivotal role in controlling gene expression and metabolic flux in the tumor context. Concurrently, the gut microbiota profoundly influences GI tumorigenesis and immune evasion by modulating metabolite availability and remodeling the tumor microenvironment. Recent evidence has uncovered a bidirectional crosstalk between microbial metabolites and m6A methylation: microbiota-derived signals dynamically regulate m6A deposition on metabolic and immune transcripts, while m6A modifications, in turn, regulate the stability and translation of key mRNAs such as PD-L1 and FOXP3. This reciprocal interaction forms self-reinforcing epigenetic circuits that drive tumor plasticity, immune escape, and metabolic adaptation. In this review, we dissect the molecular underpinnings of the microbiota-m6A-metabolism axis in GI cancers and explore its potential to inform novel strategies in immunotherapy, metabolic intervention, and microbiome-guided precision oncology.
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Affiliation(s)
- Xiuxiu Qiu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Qi Gao
- Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jiahui Wang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhanxia Zhang
- Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Li Tao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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23
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Omezzolli G, Iannello A, Vallone FE, Brandimarte L, Micillo M, Bertola N, Lavarello C, Grinovero N, Ferrero G, Mellert K, Möller P, Bruno S, Furman RR, Allan JN, Petretto A, Deaglio S, Ravera S, Vaisitti T. Complementary approaches define the metabolic features that accompany Richter syndrome transformation. Cell Mol Life Sci 2025; 82:152. [PMID: 40204982 PMCID: PMC11982009 DOI: 10.1007/s00018-025-05670-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 02/25/2025] [Accepted: 03/19/2025] [Indexed: 04/11/2025]
Abstract
Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.
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MESH Headings
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell/metabolism
- Leukemia, Lymphocytic, Chronic, B-Cell/pathology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- Animals
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Cell Transformation, Neoplastic/genetics
- Glycolysis
- Citric Acid Cycle
- Mice
- Oxidative Phosphorylation
- Glucose/metabolism
- Glutamine/metabolism
- NF-kappa B/metabolism
- NF-kappa B/antagonists & inhibitors
- Phosphatidylinositol 3-Kinases/metabolism
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Affiliation(s)
- Giulia Omezzolli
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Andrea Iannello
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Francesco E Vallone
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Lorenzo Brandimarte
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Matilde Micillo
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Nadia Bertola
- U.O. Molecular Pathology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Chiara Lavarello
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Giannina Gaslini, Genoa, Italy
| | - Nicole Grinovero
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Giannina Gaslini, Genoa, Italy
| | - Giulio Ferrero
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Kevin Mellert
- Institute of Pathology, University Hospital Ulm, Ulm, Germany
| | - Peter Möller
- Institute of Pathology, University Hospital Ulm, Ulm, Germany
| | - Silvia Bruno
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Richard R Furman
- Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY, USA
| | - John N Allan
- Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY, USA
| | - Andrea Petretto
- Core Facilities-Clinical Proteomics and Metabolomics, IRCCS Giannina Gaslini, Genoa, Italy
| | - Silvia Deaglio
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy
| | - Silvia Ravera
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Tiziana Vaisitti
- Department of Medical Sciences, University of Torino, Via Nizza 52, 10126, Turin, Italy.
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24
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Wang J, Gong P, Liu Q, Wang M, Wu D, Li M, Zheng S, Wang H, Long Q. Stimulation of regulatory dendritic cells suppresses cytotoxic T cell function and alleviates DEN-induced liver injury, fibrosis and hepatocellular carcinoma. Front Immunol 2025; 16:1565486. [PMID: 40264769 PMCID: PMC12011597 DOI: 10.3389/fimmu.2025.1565486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 03/06/2025] [Indexed: 04/24/2025] Open
Abstract
Background Dendritic cells (DCs) are versatile professional antigen-presenting cells and play an instrumental role in the generation of antigen-specific T-cell responses. Modulation of DC function holds promise as an effective strategy to improve anti-tumor immunotherapy efficacy and enhance self-antigen tolerance in autoimmune diseases. Methods Wild-type (WT) and TLR2 knockout (KO) mice at 2 weeks of age were injected intraperitoneally (i.p.) with a single dose of diethylnitrosamine (DEN) to induce hepatocellular carcinoma (HCC). Four weeks later, WT and KO mice were randomly divided into control and treatment groups and treated once every two days for 30 weeks with phosphate buffered saline (PBS) and a mix of 4 TLR2-activating lactic acid-producing probiotics (LAP), respectively. Mice were euthanized after 30 weeks of LAP treatment and their liver tissues were collected for gene expression, histological, flow cytometric and single-cell RNA sequencing analyses. Results We demonstrate here that oral administration of a mix of TLR2-activating LAP triggers a marked accumulation of regulatory DCs (rDCs) in the liver of mice. LAP-treated mice are protected from DEN-induced liver injury, fibrosis and HCC in a TLR2-dependent manner. Single-cell transcriptome profiling revealed that LAP treatment determines an immunosuppressive hepatic T-cell program that is characterized by a significantly reduced cytotoxic activity. The observed functional changes of T cells correlated well with the presence of a hepatic DC subset displaying a regulatory or tolerogenic transcriptional signature. Conclusion Overall, these data suggest that stimulation of regulatory dendritic cells (rDCs) in the liver by LAP suppresses cytotoxic T-cell function and alleviates DEN-induced liver damage, fibrosis and tumorigenesis.
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Affiliation(s)
- Junjie Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Pixu Gong
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Qingqing Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Menglei Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Dengfang Wu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Mengyu Li
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Shujie Zheng
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Han Wang
- Center for Circadian Clocks, Soochow University, Suzhou, Jiangsu, China
- School of Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Qiaoming Long
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
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25
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Cai L, Hammond NG, Tasdogan A, Alsamraae M, Yang C, Cameron RB, Quan P, Solmonson A, Gu W, Pachnis P, Kaur M, Chang BK, Zhou Q, Hensley CT, Do QN, Martins Nascentes Melo L, Ubellacker JM, Kaushik A, Clare MG, Alcazar IN, Kurylowicz K, Marcuccilli JD, Allies G, Kutritz A, Klode J, Ramesh V, Rogers TJ, Rao AD, Crentsil HE, Li H, Brister F, McDaniel P, Xu X, Evers BM, Zacharias LG, Sudderth J, Xu J, Mathews TP, Oliver D, Minna JD, Waters J, Morrison SJ, Kernstine KH, Faubert B, DeBerardinis RJ. High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non-Small Cell Lung Cancer in Patients. Cancer Discov 2025; 15:702-716. [PMID: 39960461 PMCID: PMC11962397 DOI: 10.1158/2159-8290.cd-23-1319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/22/2024] [Accepted: 01/23/2025] [Indexed: 03/01/2025]
Abstract
SIGNIFICANCE Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.
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Affiliation(s)
- Ling Cai
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Nia G. Hammond
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Alpaslan Tasdogan
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Dermatology, University Hospital Essen & German Cancer Consortium, Essen, Germany
| | - Massar Alsamraae
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Chendong Yang
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Robert B. Cameron
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Peiran Quan
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ashley Solmonson
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Wen Gu
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Panayotis Pachnis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Mayher Kaur
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Brianna K. Chang
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Qin Zhou
- Quantitative Biomedical Research Center, Peter O’Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Christopher T. Hensley
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Quyen N. Do
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | | | - Jessalyn M. Ubellacker
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Akash Kaushik
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Maia G. Clare
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Isabel N. Alcazar
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Katarzyna Kurylowicz
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Joseph D. Marcuccilli
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Gabriele Allies
- Department of Dermatology, University Hospital Essen & German Cancer Consortium, Essen, Germany
| | - Andrea Kutritz
- Department of Dermatology, University Hospital Essen & German Cancer Consortium, Essen, Germany
| | - Joachim Klode
- Department of Dermatology, University Hospital Essen & German Cancer Consortium, Essen, Germany
| | - Vijayashree Ramesh
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Thomas J. Rogers
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Aparna D. Rao
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hannah E. Crentsil
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hong Li
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Clinical Research Unit, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Fang Brister
- Clinical Research Unit, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Phyllis McDaniel
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Clinical Research Unit, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Xiaohong Xu
- Clinical Research Unit, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Bret M. Evers
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Lauren G. Zacharias
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jessica Sudderth
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jian Xu
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Thomas P. Mathews
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Dwight Oliver
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John D. Minna
- Hamon Center for Therapeutic Oncology Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - John Waters
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sean J. Morrison
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kemp H. Kernstine
- Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Brandon Faubert
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Section of Hematology and Oncology, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Ralph J. DeBerardinis
- Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas
- Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas
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26
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Zheng C, Tan H, Niu G, Huang X, Lu J, Chen S, Li H, Zhu J, Zhou Z, Xu M, Pan C, Liu J, Li J. ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2416467. [PMID: 39951294 PMCID: PMC11984883 DOI: 10.1002/advs.202416467] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/13/2025] [Indexed: 04/12/2025]
Abstract
Lactate derived from aerobic glycolysis is crucial for DNA damage repair and chemoresistance. Nevertheless, it is frequently noted that cancer cells depend on glutaminolysis to replenish essential metabolites. Whether and how glutaminolysis might enhance lactate production and facilitate DNA repair in cancer cells remains unknown. Here, it is shown that malate enzyme 2 (ME2), which metabolizes glutamine-derived malate to pyruvate, contributes to lactate production and chemotherapy resistance in ovarian cancer. Mechanistically, chemotherapy reduces the expression of glucose transporters and impairs glucose uptake in cancer cells. The resultant decrease in intracellular glucose levels triggers the acetylation of ME2 at lysine 156 by ACAT1, which in turn potentiates ME2 enzyme activity and facilitates lactate production from glutamine. ME2-derived lactate contributes to the development of acquired chemoresistance in cancer cells subjected to prolonged chemotherapy, primarily by facilitating the lactylation of proteins involved in homologous recombination repair. Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.
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Affiliation(s)
- Cuimiao Zheng
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Hao Tan
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Gang Niu
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Xi Huang
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Jingyi Lu
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Siqi Chen
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Haoyuan Li
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Jiayu Zhu
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Zhou Zhou
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Manman Xu
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Chaoyun Pan
- Department of Biochemistry and Molecular BiologyZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
- Advanced Medical Technology CenterThe First Affiliated HospitalZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
| | - Junxiu Liu
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
| | - Jie Li
- Department of Obstetrics and GynecologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhou510080China
- Advanced Medical Technology CenterThe First Affiliated HospitalZhongshan School of MedicineSun Yat‐sen UniversityGuangzhou510080China
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27
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Lv Y, Pu L, Ran B, Xiang B. Targeting tumor angiogenesis and metabolism with photodynamic nanomedicine. Front Cell Dev Biol 2025; 13:1558393. [PMID: 40235732 PMCID: PMC11996804 DOI: 10.3389/fcell.2025.1558393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Accepted: 03/24/2025] [Indexed: 04/17/2025] Open
Abstract
Photodynamic therapy (PDT) holds considerable promise as a tumor treatment modality, characterized by its targeted action, compatibility with other therapeutic approaches, and non - invasive features. PDT can achieve remarkable spatiotemporal precision in tumor ablation through the generation of reactive oxygen species (ROS). Nevertheless, despite its potential in tumor treatment, PDT encounters multiple challenges in practical applications. PDT is highly oxygen - dependent, and thus the effectiveness of PDT can be markedly influenced by tumor hypoxia. The co-existence of abnormal vasculature and metabolic deregulation gives rise to a hypoxic microenvironment, which not only sustains tumor survival but also undermines the therapeutic efficacy of PDT. Consequently, targeting tumor angiogenesis and metabolism is essential for revitalizing PDT. This review emphasizes the mechanisms and strategies for revitalizing PDT in tumor treatment, predominantly concentrating on interfering with tumor angiogenesis and reprogramming tumor cell metabolism. Lastly, the outlining future perspectives and current limitations of PDT are also summarized. This could provide new insights and methodologies for overcoming the challenges associated with PDT in tumor treatment, ultimately advancing the field of PDT.
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Affiliation(s)
- Yong Lv
- Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lihui Pu
- Department of Critical Care, West China Hospital, Sichuan University, Chengdu, China
| | - Bei Ran
- School of Biomedical Engineering, Sichuan University, Chengdu, China
| | - Bo Xiang
- Department of Pediatric Surgery, West China Hospital, Sichuan University, Chengdu, China
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28
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Gao F, Shah R, Xin G, Wang R. Metabolic Dialogue Shapes Immune Response in the Tumor Microenvironment. Eur J Immunol 2025; 55:e202451102. [PMID: 40223597 PMCID: PMC11995254 DOI: 10.1002/eji.202451102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 04/15/2025]
Abstract
The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.
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Affiliation(s)
- Fengxia Gao
- Department of Microbial Infection and ImmunityPelotonia Institute for Immuno‐OncologyThe Ohio State UniversityColumbusOhioUSA
| | - Rushil Shah
- Center for Childhood Cancer ResearchHematology/Oncology & BMTAbigail Wexner Research Institute at Nationwide Children's HospitalDepartment of PediatricsThe Ohio State UniversityColumbusOhioUSA
| | - Gang Xin
- Department of Microbial Infection and ImmunityPelotonia Institute for Immuno‐OncologyThe Ohio State UniversityColumbusOhioUSA
| | - Ruoning Wang
- Center for Childhood Cancer ResearchHematology/Oncology & BMTAbigail Wexner Research Institute at Nationwide Children's HospitalDepartment of PediatricsThe Ohio State UniversityColumbusOhioUSA
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29
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Cui Q, Li S, Liu X, Liu J, Chen W, Sheng Y, Xie P, Jin L, Zeng F, Lv F, Hu X, Xiao RP. MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia. Cell Metab 2025; 37:954-970.e8. [PMID: 40020680 DOI: 10.1016/j.cmet.2025.01.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 10/25/2024] [Accepted: 01/21/2025] [Indexed: 03/03/2025]
Abstract
Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.
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Affiliation(s)
- Qionghua Cui
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Shijin Li
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Xidan Liu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Jie Liu
- Dazhou Central Hospital, Dazhou 635000, Sichuan, China
| | - Wenxin Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Ye Sheng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Peng Xie
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Fanxin Zeng
- Dazhou Central Hospital, Dazhou 635000, Sichuan, China
| | - Fengxiang Lv
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China
| | - Xinli Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
| | - Rui-Ping Xiao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Beijing City Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China.
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30
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Hu MM, Zhao Y, Zhang N, Gong FY, Zhang W, Dong CS, Dai JF, Wang J. Tumor Microenvironment: Obstacles and Opportunities for T Cell-Based Tumor Immunotherapies. Mol Cancer Res 2025; 23:277-287. [PMID: 39898773 DOI: 10.1158/1541-7786.mcr-24-0747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 11/20/2024] [Accepted: 01/30/2025] [Indexed: 02/04/2025]
Abstract
The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.
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Affiliation(s)
- Miao-Miao Hu
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
| | - Ying Zhao
- Department of Pathophysiology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Nan Zhang
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
| | - Fang-Yuan Gong
- Department of Immunology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou, China
| | - Wei Zhang
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
| | - Chun-Sheng Dong
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jian-Feng Dai
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
| | - Jun Wang
- Institutes of Biology and Medical Sciences, MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Infection and Immunity, Suzhou Medical College of Soochow University, Suzhou, China
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31
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Moon CY, Belabed M, Park MD, Mattiuz R, Puleston D, Merad M. Dendritic cell maturation in cancer. Nat Rev Cancer 2025; 25:225-248. [PMID: 39920276 PMCID: PMC11954679 DOI: 10.1038/s41568-024-00787-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/12/2024] [Indexed: 02/09/2025]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity.
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Affiliation(s)
- Chang Yoon Moon
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Meriem Belabed
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Matthew D Park
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raphaël Mattiuz
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Puleston
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miriam Merad
- Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Sinclair LV, Cantrell DA. Protein Synthesis and Metabolism in T Cells. Annu Rev Immunol 2025; 43:343-366. [PMID: 40279310 DOI: 10.1146/annurev-immunol-082323-035253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
T lymphocytes are essential for immune responses to pathogens and tumors. Their ability to rapidly clonally expand and differentiate to effector cells following infection, and then to curb effector function following infection clearance, is fundamental for adaptive immunity. Proteome remodeling in response to immune activation is a fundamental mechanism that allows T cells to swiftly reprogram for acquisition of effector function and is possible only because antigen receptor- and cytokine-driven signal transduction pathways can trigger massive increases in protein synthesis. Equally, the ability to repress protein synthesis supports a return to quiescence once pathogens are cleared to avoid autoimmunity and to generate memory T cell populations. This review discusses what is known about T cell proteomes and the regulatory mechanisms that control protein synthesis in T cells. The focus is on how this fundamental process is dynamically controlled to ensure immune homeostasis.
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Affiliation(s)
- Linda V Sinclair
- Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom;
| | - Doreen A Cantrell
- Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom;
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Hua Q, Li Z, Weng Y, Wu Y, Zheng L. Myeloid cells: key players in tumor microenvironments. Front Med 2025; 19:265-296. [PMID: 40048137 DOI: 10.1007/s11684-025-1124-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 12/16/2024] [Indexed: 05/04/2025]
Abstract
Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.
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Affiliation(s)
- Qiaomin Hua
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Zhixiong Li
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yulan Weng
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China
| | - Yan Wu
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
| | - Limin Zheng
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, China.
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Buj R, Cole AR, Danielson J, Xu J, Hurd D, Kishore A, Kedziora KM, Chen J, Yang B, Barras D, Uboveja A, Amalric A, Apiz Saab JJ, Wickramasinghe J, Tangudu NK, Levasseur E, Wang H, Minasyan A, Dadey RE, Sharrow AC, Kunning S, Vendetti FP, Rivadeneira DB, Bakkenist CJ, Bruno TC, Delgoffe GM, Hempel N, Snyder NW, Bao R, Soloff AC, Kirk-Wood JM, Dangaj Laniti D, Kossenkov AV, Muir A, Das J, Davar D, Mesaros C, Aird KM. CDKN2A Low cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.08.637227. [PMID: 39975044 PMCID: PMC11839072 DOI: 10.1101/2025.02.08.637227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.
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Mao X, Huang L, Liu X, Lin X, Wu Q, Wang X, Ren Y, Ma J, Zhang M, Lin Y, Ralser DJ, Mustea A, Chen G, Sun P. High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy-lysosomal pathway in endometrial cancer. Cell Death Dis 2025; 16:182. [PMID: 40097416 PMCID: PMC11914573 DOI: 10.1038/s41419-025-07499-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 03/05/2025] [Indexed: 03/19/2025]
Abstract
Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769HK2 vs. ARG 313HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.
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Affiliation(s)
- Xiaodan Mao
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Lixiang Huang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Xianhua Liu
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
- Pathology Department, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, China
| | - Xite Lin
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Qibin Wu
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Xinrui Wang
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Medical Research Center, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350013, China
| | - Yuan Ren
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Jincheng Ma
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Maotong Zhang
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China
| | - Yao Lin
- Fujian-Macao Science and Technology Cooperation Base of Traditional Chinese Medicine-Oriented Chronic Disease Prevention and Treatment, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China
| | - Damian J Ralser
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Alexander Mustea
- Department of Gynecology and Gynecological Oncology, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Gang Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Pengming Sun
- Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, 350001, Fujian, China.
- Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children's Hospital), Fuzhou, 350001, Fujian, China.
- Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, 350001, Fujian, China.
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Cabezón-Gutiérrez L, Palka-Kotlowska M, Custodio-Cabello S, Chacón-Ovejero B, Pacheco-Barcia V. Metabolic mechanisms of immunotherapy resistance. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2025; 6:1002297. [PMID: 40092297 PMCID: PMC11907103 DOI: 10.37349/etat.2025.1002297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 02/22/2025] [Indexed: 03/19/2025] Open
Abstract
Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.
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Affiliation(s)
- Luis Cabezón-Gutiérrez
- Medical Oncology, Hospital Universitario De Torrejón, 28850 Madrid, Spain
- Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain
| | - Magda Palka-Kotlowska
- Medical Oncology, Hospital Universitario De Torrejón, 28850 Madrid, Spain
- Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain
| | - Sara Custodio-Cabello
- Medical Oncology, Hospital Universitario De Torrejón, 28850 Madrid, Spain
- Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain
| | - Beatriz Chacón-Ovejero
- Department of Pharmacy and Nutrition, Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid, 28670 Madrid, Spain
| | - Vilma Pacheco-Barcia
- Medical Oncology, Hospital Universitario De Torrejón, 28850 Madrid, Spain
- Facultad de Medicina, Universidad Francisco de Vitoria, 28223 Madrid, Spain
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37
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Wang N, Lu S, Cao Z, Li H, Xu J, Zhou Q, Yin H, Qian Q, Zhang X, Tao M, Jiang Q, Zhou P, Zheng L, Han L, Li H, Yin L, Gu Y, Dou X, Sun H, Wang W, Piao HL, Li F, Xu Y, Yang W, Chen S, Liu J. Pyruvate metabolism enzyme DLAT promotes tumorigenesis by suppressing leucine catabolism. Cell Metab 2025:S1550-4131(25)00066-X. [PMID: 40112809 DOI: 10.1016/j.cmet.2025.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 11/24/2024] [Accepted: 02/22/2025] [Indexed: 03/22/2025]
Abstract
Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.
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Affiliation(s)
- Ning Wang
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Sijia Lu
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Ziyi Cao
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Huimin Li
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
| | - Junting Xu
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Qian Zhou
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hanrui Yin
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Qiqi Qian
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Xianjing Zhang
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Mijia Tao
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Quanxin Jiang
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Peihui Zhou
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Liaoyuan Zheng
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Liu Han
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hongtao Li
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Limin Yin
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Yunqing Gu
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Xuefeng Dou
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Haipeng Sun
- Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Wei Wang
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hai-Long Piao
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Fuming Li
- Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China
| | - Yingjie Xu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiwei Yang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Suzhen Chen
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Junli Liu
- Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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38
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Schild T, Wallisch P, Zhao Y, Wang YT, Haughton L, Chirayil R, Pierpont K, Chen K, Nunes-Violante S, Cross J, de Stanchina E, Thompson CB, Scheinberg DA, Perry JSA, Keshari KR. Metabolic engineering to facilitate anti-tumor immunity. Cancer Cell 2025; 43:552-562.e9. [PMID: 40020672 PMCID: PMC11929521 DOI: 10.1016/j.ccell.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 10/23/2024] [Accepted: 02/05/2025] [Indexed: 03/03/2025]
Abstract
Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME.
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Affiliation(s)
- Tanya Schild
- Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Patrick Wallisch
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA
| | - Yixuan Zhao
- Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ya-Ting Wang
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lyric Haughton
- Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rachel Chirayil
- Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Kaitlyn Pierpont
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA
| | - Kevin Chen
- Anti-tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Sara Nunes-Violante
- Metabolism Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Justin Cross
- Metabolism Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Elisa de Stanchina
- Anti-tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Craig B Thompson
- Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David A Scheinberg
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA; Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Justin S A Perry
- Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Kayvan R Keshari
- Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Gerstner Sloan Kettering School for Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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39
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Xie X, Liu W, Yuan Z, Chen H, Mao W. Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications. Mol Cancer 2025; 24:71. [PMID: 40057791 PMCID: PMC11889836 DOI: 10.1186/s12943-025-02269-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/11/2025] [Indexed: 04/02/2025] Open
Abstract
Epigenomic modifications-such as DNA methylation, histone acetylation, and histone methylation-and their implications in tumorigenesis, progression, and treatment have emerged as a pivotal field in cancer research. Tumors undergo metabolic reprogramming to sustain proliferation and metastasis in nutrient-deficient conditions, while suppressing anti-tumor immunity in the tumor microenvironment (TME). Concurrently, immune cells within the immunosuppressive TME undergo metabolic adaptations, leading to alterations in their immune function. The complicated interplay between metabolites and epigenomic modulation has spotlighted the significance of epigenomic regulation in tumor immunometabolism. In this review, characteristics of the epigenomic modification associated with tumors are systematically summarized alongside with their regulatory roles in tumor metabolic reprogramming and immunometabolism. Classical and emerging approaches are delineated to broaden the boundaries of research on the crosstalk research on the crosstalk between tumor immunometabolism and epigenomics. Furthermore, we discuss potential therapeutic strategies that target tumor immunometabolism to modulate epigenomic modifications, highlighting the burgeoning synergy between metabolic therapies and immunotherapy as a promising avenue for cancer treatment.
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Affiliation(s)
- Xiaowen Xie
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
| | - Weici Liu
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China
- Center of Clinical Research, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Zhiyuan Yuan
- Institute of Science and Technology for Brain-Inspired Intelligence; MOE Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence; MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, China.
| | - Hanqing Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Capital Medical University, Beijing, 100069, China.
| | - Wenjun Mao
- Department of Thoracic Surgery, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, China.
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Sun L, Sun Y, Zuo K, Fan L, Wang X, Zhang J, Hu S, Liu X, Li J, Li Y, Shao Z, Xu X, Wu A, Song S. Pilot Study of Nectin-4-Targeted PET Imaging Agent 68Ga-FZ-NR-1 in Triple-Negative Breast Cancer from Bench to First-in-Human. J Nucl Med 2025; 66:473-479. [PMID: 39947908 DOI: 10.2967/jnumed.124.269024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/14/2025] [Indexed: 03/05/2025] Open
Abstract
Nectin cell adhesion molecule 4 (Nectin-4) is an emerging biomarker for cancer diagnosis and therapy. We developed a Nectin-4-targeted 68Ga-DOTA-Sar10-Nectin-4 (68Ga-FZ-NR-1) PET/CT radiotracer for detecting Nectin-4 expression in a tumor model and in triple-negative breast cancer (TNBC) patients. Methods: A series of Nectin-4-targeted radiotracers-68Ga-FZ-NR-1, 68Ga-DOTA-polyethylene glycol 5-Nectin-4 (68Ga-FZ-NR-2), and 68Ga-DOTA-polyethylene glycol 10-Nectin-4 (68Ga-FZ-NR-3)-were synthesized, and their targeting ability and specificity were evaluated in vitro and in vivo. In vitro experiments were performed in the MDA-MB-468 (Nectin-4-positive) and MDA-MB-231 (Nectin-4-negative) cell lines. PET/CT imaging in tumor models was performed to assess the Nectin-4-targeting ability of the radiotracers. After preclinical experiments and screening, the 68Ga-FZ-NR-1 radiotracer was selected for safety and efficacy evaluation in a first-in-human trial in TNBC patients. Positive lesions were biopsied and analyzed by immunohistochemistry to determine Nectin-4 expression levels. Results: The 3 68Ga-labeled radiotracers exhibited high radiochemical purity, stability, and strong affinity for Nectin-4. In vitro cell uptake studies showed that the radiotracers effectively targeted Nectin-4 in MDA-MB-468 cells, and 68Ga-FZ-NR-1 showed the highest targeting efficacy. In the MDA-MB-468 tumor model, PET/CT imaging showed that 68Ga-FZ-NR-1 was taken up at higher rates than 68Ga-FZ-NR-2 and 68Ga-FZ-NR-3, and it exhibited favorable pharmacokinetics and safety profiles. 68Ga-FZ-NR-1 was thus selected for subsequent clinical trials. 68Ga-FZ-NR-1 PET/CT effectively identified tumors in 9 patients with TNBC, which was confirmed by 18F-FDG PET/CT. Biopsy samples of the tumor lesions revealed that the positive lesions identified by 68Ga-FZ-NR-1 PET/CT corresponded to areas of high Nectin-4 expression. Conclusion: A series of Nectin-4-targeted radiotracers (68Ga-FZ-NR-1, 68Ga-FZ-NR-2, and 68Ga-FZ-NR-3) was developed and evaluated. Preclinical studies demonstrated that 68Ga-FZ-NR-1 can identify tumors with high Nectin-4 expression. In a preliminary clinical study, 68Ga-FZ-NR-1 was used to effectively identify and visualize Nectin-4-expressing tumor lesions in patients with TNBC, which was confirmed by immunohistochemistry. This radiotracer provides a noninvasive approach to the assessment of Nectin-4 and a potential basis for the development of Nectin-4-targeted treatments for TNBC.
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Affiliation(s)
- Li Sun
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, and Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi, China
| | - Yuyun Sun
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Ke Zuo
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lei Fan
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiao Wang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jianping Zhang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Silong Hu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Xiaosheng Liu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Jindian Li
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Ye Li
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Zhiming Shao
- Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaoping Xu
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
| | - Aiguo Wu
- Ningbo Key Laboratory of Biomedical Imaging Probe Materials and Technology, CAS Key Laboratory of Magnetic Materials and Devices, and Laboratory of Advanced Theranostic Materials and Technology, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, China
- Zhejiang International Cooperation Base of Biomedical Materials Technology and Application, Zhejiang Engineering Research Center for Biomedical Materials, Ningbo Cixi Institute of Biomedical Engineering, Cixi, China
| | - Shaoli Song
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China;
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China
- Center for Biomedical Imaging, Fudan University, Shanghai, China; and
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Luo J, Guo M, Huang M, Liu Y, Qian Y, Liu Q, Cao X. Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation. Signal Transduct Target Ther 2025; 10:78. [PMID: 40025022 PMCID: PMC11873268 DOI: 10.1038/s41392-025-02158-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 11/22/2024] [Accepted: 01/22/2025] [Indexed: 03/04/2025] Open
Abstract
Adoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having superior antitumor activity against pancreatic cancer and ovarian cancer. Mechanistically, Neo-2/15 provided sustained and enhanced downstream IL-2 receptor signaling, which promotes the expression of c-Myc and nuclear respiratory factor 1 (NRF1) in CAR-NK cells. This upregulation was crucial for maintaining mitochondrial adaptability and metabolic resilience, ultimately leading to increased cytotoxicity and pronounced persistence of CAR-NK cells within the TME. The resistance against TME immunosuppressive polarization necessitated the upregulation of NRF1, which is essential to the augmentative effects elicited by Neo-2/15. Overexpression of NRF1 significantly bolsters the antitumor efficacy of CAR-NK cells both in vitro and in vivo, with increased ATP production. Collectively, Neo-2/15-expressing CAR-NK cells exerts superior antitumor effects by exhaustion-resistance and longer survival in solid tumors.
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Affiliation(s)
- Jianhua Luo
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China
| | - Meng Guo
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China.
| | - Mingyan Huang
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China
| | - Yanfang Liu
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China
- Department of Pathology, Changhai Hospital, Navy Medical University, Shanghai, 200433, China
| | - Yuping Qian
- Department of Pathology, Changhai Hospital, Navy Medical University, Shanghai, 200433, China
| | - Qiuyan Liu
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China.
| | - Xuetao Cao
- National Key Laboratory of Immunity & Inflammation, Institute of Immunology, Navy Medical University, Shanghai, 200433, China.
- Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China.
- Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
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Zeng L, Zhang J, Song R, Dong X, Wei Z, Li X, Zeng X, Yao J. Laminarin Alleviates Acute Lung Injury Induced by LPS Through Inhibition of M1 Macrophage Polarisation. J Cell Mol Med 2025; 29:e70440. [PMID: 40045157 PMCID: PMC11882389 DOI: 10.1111/jcmm.70440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 12/27/2024] [Accepted: 02/12/2025] [Indexed: 03/09/2025] Open
Abstract
The lipopolysaccharide-induced acute lung injury (ALI) mouse model is used to simulate human acute respiratory distress syndrome (ARDS), which has a high mortality rate. An imbalance between M1 and M2 macrophages, characterised by an increase in M1 macrophages, was observed in sepsis-induced ALI. We report that laminarin, an active ingredient found in algae, exhibits exceptional performance in a mouse model of sepsis-induced ALI. It ameliorates lung edema, enhances the survival rate of mice and reduces the levels of the inflammatory factors TNF-α and IL-6. Furthermore, laminarin reduced the expression of CD86, which are markers associated with M1 macrophages. Laminarin treatment reduces the secretion of TNF-α and IL-6 in LPS-stimulated macrophages. Laminarin treatment also decreases glucose uptake in LPS-stimulated macrophages. Transcriptome sequencing reveals that genes downregulated in LPS-stimulated macrophages following laminarin treatment are predominantly enriched in the HIF-1α signalling pathway. Experimental validation confirms that laminarin treatment of LPS-stimulated macrophages reduces the expression of HIF-1α and significantly decreases the expression of related indicators ROS and NLRP3. After using siRNA to knock down HIF-1α in RAW264.7 cells, the inhibitory effect of laminarin on LPS-induced M1 polarisation of macrophages is abolished. This suggests that laminarin may potentially inhibit macrophage polarisation towards the M1 phenotype by downregulating the HIF-1α signal. In conclusion, the data presented in our study demonstrate that laminarin can effectively reduce M1 macrophage polarisation by downregulating HIF-1α signalling. This makes it a novel candidate drug for the treatment of LPS-induced ALI.
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Grants
- 2020KTSCX024 Educational Commission of Guangdong Province, China
- 2022A1515220197 Basic and Applied Basic Research Foundation of Guangdong Province
- 2021A1515010928 Natural Science Foundation of Guangdong Province, China
- B2021121 The Medical Science and Technology Foundation of Guangdong Province
- YNZX0003 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- YNZX0002 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- SRSP2021015 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- SRSP2021002 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- SRSP2021006 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- SRSP2019009 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- SRSP2021012 The Scientific Research Start Plan of Shunde Hospital, Southern Medical University
- Educational Commission of Guangdong Province, China
- Basic and Applied Basic Research Foundation of Guangdong Province
- Natural Science Foundation of Guangdong Province, China
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Affiliation(s)
- Liming Zeng
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
| | - Jieyu Zhang
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
- Central Laboratory of The Sixth Affliated Hospital, School of MedicineSouth China University of TechnologyFoshanGuangdongChina
| | - Rongrong Song
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
- Central Laboratory of The Sixth Affliated Hospital, School of MedicineSouth China University of TechnologyFoshanGuangdongChina
| | - Xinhuai Dong
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
| | - Zibo Wei
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
| | - Xiaoyan Li
- Clinical Laboratory of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
| | - Xiaokang Zeng
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
- Central Laboratory of The Sixth Affliated Hospital, School of MedicineSouth China University of TechnologyFoshanGuangdongChina
| | - Jie Yao
- Medical Research Center & Department of Laboratory Medicine of Shunde HospitalSouthern Medical University (The First People's Hospital of Shunde)FoshanGuangdongChina
- Clinical Laboratory of The Sixth Affiliated Hospital, School of MedicineSouth China University of TechnologyFoshanGuangdongChina
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Li X, Chen Y, Li X, Yang X, Zhou L, Cheng Y, Hou H, Yang D, Gong Y, Xiao H, Wang J. Weight Management for Fertility-Preservation Therapy in Endometrial Cancer: Opportunities and Challenges. Curr Oncol Rep 2025; 27:195-210. [PMID: 39913071 DOI: 10.1007/s11912-025-01635-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 02/07/2025]
Abstract
PURPOSE OF REVIEW Obesity is increasingly recognized as a significant factor impacting the outcomes of fertility-preserving therapies for endometrial cancer (EC). This review explores the effects of glycolipid metabolism on EC and its relationship with body weight. We will examine how excess body weight influences the effectiveness of fertility-preserving treatments and discuss potential mechanisms for effective weight management. Additionally, the review highlights the importance of comprehensive weight management as an adjunct strategy to enhance the efficacy of fertility-preserving interventions, providing insights into how to integrate metabolic health into clinical treatment protocols. RECENT FINDINGS Weight management can modify the tumor microenvironment by depriving the tumor of nutrients, whereas exercise can enhance immunity, potentially leading to tumor cell death. In addition, progesterone therapy may impede the proliferation of EC cells. Comprehensive weight management can serve as an essential adjuvant treatment for patients undergoing fertility-preserving therapies for EC. In this review, we highlight that comprehensive weight management can serve as a crucial adjuvant treatment for patients undergoing fertility-preserving therapies for endometrial cancer. Targeting glycolipid metabolism and addressing adiposity can improve hormonal balance, reduce inflammation, and enhance fertility outcomes. Further research is necessary to establish specific protocols and evaluate the effectiveness of these strategies in clinical practice.
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Affiliation(s)
- XiaoDan Li
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - YiQian Chen
- Beijing Health Vocational College, Beijing, 101101, China
| | - XiaoWei Li
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Xiao Yang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Ling Zhou
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Yuan Cheng
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - HongYi Hou
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Dandan Yang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Yuanyuan Gong
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China
| | - Haihua Xiao
- Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
| | - Jianliu Wang
- Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing, 100044, China.
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Yuan Z, Yu T, Wang X, Meng K, Wang T, Wang B, Xi Y, Wang C, Zeng C, Hu S, Tian Y, Xiong H, Wang Q, Zou W, Wang X, Gao Y, Fu X, Li L. Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells. Pharmacol Res 2025; 213:107643. [PMID: 39909124 DOI: 10.1016/j.phrs.2025.107643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/26/2025] [Accepted: 02/02/2025] [Indexed: 02/07/2025]
Abstract
Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.
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Affiliation(s)
- Zhiwei Yuan
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Taiyan Yu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xu Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kelin Meng
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tianlai Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Boyu Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Xi
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Congjian Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chenxi Zeng
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaojie Hu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yitao Tian
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hui Xiong
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qi Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenbin Zou
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xue Wang
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Gao
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiangning Fu
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Lequn Li
- Thoracic Surgery Laboratory, Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Xu J, Zhao Y, Tyler Mertens R, Ding Y, Xiao P. Sweet regulation - The emerging immunoregulatory roles of hexoses. J Adv Res 2025; 69:361-379. [PMID: 38631430 PMCID: PMC11954837 DOI: 10.1016/j.jare.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 03/20/2024] [Accepted: 04/13/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND It is widely acknowledged that dietary habits have profound impacts on human health and diseases. As the most important sweeteners and energy sources in human diets, hexoses take part in a broad range of physiopathological processes. In recent years, emerging evidence has uncovered the crucial roles of hexoses, such as glucose, fructose, mannose, and galactose, in controlling the differentiation or function of immune cells. AIM OF REVIEW Herein, we reviewed the latest research progresses in the hexose-mediated modulation of immune responses, provided in-depth analyses of the underlying mechanisms, and discussed the unresolved issues in this field. KEY SCIENTIFIC CONCEPTS OF REVIEW Owing to their immunoregulatory effects, hexoses affect the onset and progression of various types of immune disorders, including inflammatory diseases, autoimmune diseases, and tumor immune evasion. Thus, targeting hexose metabolism is becoming a promising strategy for reversing immune abnormalities in diseases.
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Affiliation(s)
- Junjie Xu
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuening Zhao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | - Yimin Ding
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Peng Xiao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; The Key Laboratory for Immunity and Inflammatory Diseases of Zhejiang Province, Hangzhou, China.
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Zhang N, Ping W, Xiang J, Chu S, Li D, Ning S, Zhu D, Zeng W, Xu Q. Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy. Adv Healthc Mater 2025; 14:e2401362. [PMID: 39363640 DOI: 10.1002/adhm.202401362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 09/08/2024] [Indexed: 10/05/2024]
Abstract
Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.
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Affiliation(s)
- Ni Zhang
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China
| | - Wei Ping
- Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China
| | - Jingfeng Xiang
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Sitong Chu
- Department of Breast Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, 150081, China
| | - Dan Li
- Department of Breast Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530003, China
| | - Shipeng Ning
- Department of Breast Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530003, China
| | - Daoming Zhu
- Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Wen Zeng
- Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Qingyong Xu
- Department of Breast Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, 150081, China
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47
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Mohd Sahardi NFN, Priya M, Makpol S, Shafiee MN. Clinical translation of metabolomics markers in endometrial carcinoma. J Obstet Gynaecol Res 2025; 51:e16246. [PMID: 40015330 DOI: 10.1111/jog.16246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/09/2025] [Indexed: 03/01/2025]
Abstract
OBJECTIVE This comprehensive review highlights the current research on metabolomics and the metabolic pathways involved in endometrial cancer (EC), offering potential non-invasive biomarkers for EC. METHODS The data was extracted from published manuscripts between 2015 and 2024 using the reputed search engine "Pubmed." All gathered data were organized into a single table, facilitating a comparison with earlier findings. RESULTS The results of this study revealed most metabolites identified in previous metabolomic research on EC are associated with lipid, glucose, and amino acid metabolism. CONCLUSION Therefore, understanding these metabolic pathway alterations in EC is crucial for improving diagnosis, prognosis, and treatments by specially targeting these metabolic pathways.
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Affiliation(s)
| | - Manishaa Priya
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Suzana Makpol
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Mohamad Nasir Shafiee
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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48
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Shi J, Han W, Wang J, Kong X. Anti-Tumor Strategies Targeting Nutritional Deprivation: Challenges and Opportunities. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2415550. [PMID: 39895165 DOI: 10.1002/adma.202415550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 01/04/2025] [Indexed: 02/04/2025]
Abstract
Higher and richer nutrient requirements are typical features that distinguish tumor cells from AU: cells, ensuring adequate substrates and energy sources for tumor cell proliferation and migration. Therefore, nutrient deprivation strategies based on targeted technologies can induce impaired cell viability in tumor cells, which are more sensitive than normal cells. In this review, nutrients that are required by tumor cells and related metabolic pathways are introduced, and anti-tumor strategies developed to target nutrient deprivation are described. In addition to tumor cells, the nutritional and metabolic characteristics of other cells in the tumor microenvironment (including macrophages, neutrophils, natural killer cells, T cells, and cancer-associated fibroblasts) and related new anti-tumor strategies are also summarized. In conclusion, recent advances in anti-tumor strategies targeting nutrient blockade are reviewed, and the challenges and prospects of these anti-tumor strategies are discussed, which are of theoretical significance for optimizing the clinical application of tumor nutrition deprivation strategies.
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Affiliation(s)
- Jinsheng Shi
- Qingdao Key Lab of Common Diseases, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266000, China
| | - Wei Han
- Qingdao Key Lab of Common Diseases, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong, 266000, China
| | - Jie Wang
- Pharmacy Department, Qingdao Traditional Chinese Medicine Hospital (Qingdao Hiser Hospital), Qingdao, Shandong, 266000, China
| | - Xiaoying Kong
- Institute of Regenerative Medicine and Laboratory Technology Innovation, Qingdao University, Qingdao, Shandong, 266071, China
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49
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Tan H, Cai M, Wang J, Yu T, Xia H, Zhao H, Zhang X. Harnessing Macrophages in Cancer Therapy: from Immune Modulators to Therapeutic Targets. Int J Biol Sci 2025; 21:2235-2257. [PMID: 40083710 PMCID: PMC11900799 DOI: 10.7150/ijbs.106275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Accepted: 02/14/2025] [Indexed: 03/16/2025] Open
Abstract
Macrophages, as the predominant phagocytes, play an essential role in pathogens defense and tissue homeostasis maintenance. In the context of cancer, tumor-associated macrophages (TAMs) have evolved into cunning actors involved in angiogenesis, cancer cell proliferation and metastasis, as well as the construction of immunosuppressive microenvironment. Once properly activated, macrophages can kill tumor cells directly through phagocytosis or attack tumor cells indirectly by stimulating innate and adaptive immunity. Thus, the prospect of targeting TAMs has sparked significant interest and emerged as a promising strategy in immunotherapy. In this review, we summarize the diverse roles and underlying mechanisms of TAMs in cancer development and immunity and highlight the TAM-based therapeutic strategies such as inhibiting macrophage recruitment, inhibiting the differentiation reprogramming of TAMs, blocking phagocytotic checkpoints, inducing trained macrophages, as well as the potential of engineered CAR-armed macrophages in cancer therapy.
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Affiliation(s)
- Huabing Tan
- Department of Infectious Diseases, Hepatology Institute, Renmin Hospital, Shiyan Key Laboratory of Virology, Hubei University of Medicine, Shiyan, Hubei Province, China
- General internal medicine, Wuhan Jinyintan Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
| | - Meihe Cai
- Department of Traditional Chinese Medicine, Zhushan Renmin Hospital, Zhushan, 442200, China
| | | | - Tao Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Houjun Xia
- Center for Cancer Immunology, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Huanbin Zhao
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Present: Division of Pharmaceutical Sciences, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Xiaoyu Zhang
- Department of Gastrointestinal Surgery, Huai'an Second People's Hospital, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China
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50
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Cote AL, Munger CJ, Ringel AE. Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions. Cell Rep 2025; 44:115234. [PMID: 39862435 DOI: 10.1016/j.celrep.2025.115234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/24/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.
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Affiliation(s)
- Andrea L Cote
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Chad J Munger
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA
| | - Alison E Ringel
- Ragon Institute of Mass General, MIT, and Harvard, 600 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA.
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