bims-glucam 2025-04-20 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–04–20
fourteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.
KLF6-mediated glutamine metabolism governs odontogenic differentiation and matrix mineralization of dental pulp stem cells.
Viral manipulation of host cell glutamine metabolism and glutamine rewiring in hepatic diseases: Editorial on "GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome".
Cirsiliol suppresses malignant progression of hepatocellular carcinoma via regulation of glutamine metabolism.
GOT2: New therapeutic target in pancreatic cancer.
Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.
Mitochondrial glutamine metabolism drives epileptogenesis in primary hippocampal neurons.
Impacts of Radiation on Metabolism and Vascular Cell Senescence.
Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.
Emodin and Aloe-Emodin Reduce Cell Growth and Disrupt Metabolic Plasticity in Human Melanoma Cells.
UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.
Tumor-microenvironment-driven carbon-center radical generation accompanied by glutathione exhaustion for intensified chemodynamic therapy.
The impact of metabolic reprogramming on tertiary lymphoid structure formation: enhancing cancer immunotherapy.
Fumarate integrates metabolism and immunity in diseases.

J Microbiol Biotechnol. 2025 Apr 10. 35 e2412032

Inhibition of GLS1 and ASCT2 Synergistically Enhances the Anticancer Effects in Pancreatic Cancer Cells.

Dong-Hwan Kim, Dong Joon Kim, Seong-Jun Park, Won-Jun Jang, Chul-Ho Jeong.

  Pancreatic cancer, a leading cause of cancer-related deaths, is characterized by increased dependence on glutamine metabolism. Telaglenastat (CB-839), a glutaminase (GLS) inhibitor targets glutamine metabolism; however, its efficacy as monotherapy is limited owing to metabolic adaptations. In this study, we demonstrated that CB-839 effectively inhibited cell growth in pancreatic cancer cells, but activated the general control nonderepressible 2 (GCN2)-activating transcription factor 4 (ATF4) signaling pathway. ATF4 knockdown reduced glutamine transporter alanine, serine, and cysteine transporter 2 (ASCT2) expression, glutamine uptake, and cell viability under glutamine deprivation-recovery conditions, confirming its protective role in mitigating glutamine-related metabolic stress. Notably, the combination of CB-839 and the ASCT2 inhibitor V-9302 demonstrated a synergistic effect, significantly suppressing pancreatic cancer cell survival. These findings highlight ATF4 and ASCT2 as crucial therapeutic targets and indicate that dual inhibition of GLS and ASCT2 may enhance treatment outcomes for pancreatic cancer.

Keywords:  ATF4; CB-839; Pancreatic cancer; V-9302; glutamine metabolism

DOI:  https://doi.org/10.4014/jmb.2412.12032
Stem Cell Res Ther. 2025 Apr 15. 16(1): 179

KLF6-mediated glutamine metabolism governs odontogenic differentiation and matrix mineralization of dental pulp stem cells.

Wenzhi Wu, Zekai Xu, Yulian Zhang, Xiatong Zhang, Xiaoyuan Huang, Zhijian Xie, Zhuo Chen.

   BACKGROUND: When a tooth suffers severe injuries, dental pulp stem cells migrate and differentiate into odontoblast-like cells to form restorative dentin. Kruppel-like factor 6 (KLF6) activates the odontoblast differentiation of dental papilla cells during tooth development. However, the mechanisms by which KLF6 regulates the function of odontoblast-like cells differentiated from human dental pulp stem cells (hDPSCs) remain unknown.
METHODS: KLF6 was over-expressed or silenced by lentivirus transfection. Transcriptome sequencing and metabolomics were performed to reveal main changes in KLF6 high expressed hDPSCs. Mitochondrial morphology was observed by confocal microscope and cryo-transmission electron microscopy. Metabolic assays and metabolic flux were used to determine changes in cellular metabolic characteristics. Glutamine, glutamate, α-KG, and citrate concentrations were detected in cultured cells. Citrate and Ca concentration were detected in ECM. Adeno-associated virus were used to silence KLF6 in mice. A mouse dental injury model was established to investigate the role of KLF6 and glutamine metabolism in dentin repair in vivo.
RESULTS: RNA sequencing and metabolomics showed a remarkable influence on glutamine metabolism, mitochondrial respiration, and the TCA cycle by KLF6 overexpression. Metabolic assays and mitochondrial morphology observation found KLF6 promoted glutamine metabolism and mitochondrial function, and glutamine metabolism and mitochondrial respiration are enhanced during odontogenic differentiation of hDPSCs. Deprivation of glutamine inhibited mineralization of hDPSCs and restrained deposition of citrate and Ca in ECM. Increased glutamine entry into the tricarboxylic acid (TCA) cycle was both observed in differentiated hDPSCs and KLF6 overexpressed hDPSCs. ChIP-qPCR experiments revealed that KLF6 can directly bind to the promoter sequences of GLS1 and GDH. Supplementation of α-KG rescued suppression of odontogenic differentiation and mineralization induced by KLF6 knockdown. Inhibition of glutamine metabolism and knockdown of KLF6 attenuated tertiary dentin formation in vivo.
CONCLUSIONS: Our study shows that KLF6 mediates biomineralization in the newly generated functional odontoblast-like cells differentiated from hDPSCs by altering cell metabolism preferences. KLF6 facilitated glutamine influx into the TCA cycle, leading to increased deposition of citrate in the ECM.These findings may inspire the development of novel strategies for reparative dentin formation.

Keywords:  Glutamine metabolism; Kruppel-like factor 6; Odontogenic differentiation; Pulp dentin regeneration; TCA cycle

DOI:  https://doi.org/10.1186/s13287-025-04308-3
Clin Mol Hepatol. 2025 Apr 11.

Viral manipulation of host cell glutamine metabolism and glutamine rewiring in hepatic diseases: Editorial on "GDH1-dependent α-ketoglutarate promotes HBV transcription by modulating histone methylations on the cccDNA minichromosome".

Mehrangiz Dezhbord, Kyun-Hwan Kim.



Keywords:   GDH1; histone methylations; Hepatitis B virus

DOI:  https://doi.org/10.3350/cmh.2025.0366
Am J Transl Res. 2025 ;17(3): 2145-2153

Cirsiliol suppresses malignant progression of hepatocellular carcinoma via regulation of glutamine metabolism.

Bin Zhang, Jianbo Zheng, Siming Zheng.

   BACKGROUND: To investigate the therapeutic potential of cirsiliol in hepatocellular carcinoma (HCC), focusing on its impact on glutamine metabolism.
METHODS: HCC cell lines HCCLM3 and Huh7 were treated with cirsiliol, and cell viability and proliferation were assessed using CCK-8 assay. Intracellular concentrations of glutamine, α-ketoglutaric acid (α-KG), and adenosine triphosphate (ATP) were measured to evaluate glutamine metabolism. A xenograft tumor model was employed to examine the in vivo effects of cirsiliol. Additionally, network pharmacological analysis was used to identify potential targets of cirsiliol in HCC. Western blotting was conducted to analyze the modulation of the PI3K/AKT signaling pathway by cirsiliol.
RESULTS: Cirsiliol significantly inhibited HCC cell growth both in vitro and in vivo while reducing levels of glutamine, α-KG, and ATP, indicating suppression of glutamine metabolism. Activation of the PI3K signaling pathway reversed the inhibitory effects of cirsiliol on HCC cell growth and metabolism.
CONCLUSION: Cirsiliol suppresses glutamine metabolism and inhibits the growth of HCC cells by modulating the PI3K/AKT signaling pathway.

Keywords:  Hepatocellular carcinoma; PI3K; cirsiliol; glutamine metabolism

DOI:  https://doi.org/10.62347/AOTY4308
Genes Dis. 2025 Jul;12(4): 101370

GOT2: New therapeutic target in pancreatic cancer.

Jiarui Bu, Zeyu Miao, Qing Yang.

  In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.

Keywords:  GOT2; Glutamine metabolism; PPARδ; Pancreatic cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.gendis.2024.101370
Int J Gynecol Cancer. 2024 Nov;pii: S1048-891X(25)00135-5. [Epub ahead of print]34(11): 1737-1744

Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer.

Shiho Asaka, Neha Verma, Ting-Tai Yen, Jessica L Hicks, Hiro Nonogaki, Yao-An Shen, Jiaxin Hong, Ryoichi Asaka, Angelo M DeMarzo, Tian-Li Wang, Ie-Ming Shih, Stephanie Gaillard.

   OBJECTIVE: Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.
METHODS: Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score<median) endometrial cancers. We also evaluated data from The Cancer Genome Atlas (TCGA) for 527 endometrial cancer patients in whom RNA-Seq for glutaminase expression was performed and compared long-term clinical outcomes between glutaminase-high (RNA-Seq Z-score≥median) versus glutaminase-low (RNA-Seq score<median) patients.
RESULTS: In the tissue microarray analysis, glutaminase expression was positively correlated with c-Myc expression (r=0.4226, p<0.0001). Glutaminase-high endometrial cancers were associated with non-endometrioid histology (p=0.0001), high histologic grade (p=0.0004), myometrial invasion (p=0.017), advanced stage (p=0.012), increased FoxP3+ regulatory T cells (p=0.008), increased CD68+ tumor-associated macrophages (p=0.010), and higher PD-L1 combined positive scores (p=0.043). In the TCGA analysis, glutaminase-high (RNA-Seq Z-score≥median) patients showed worse overall (p=0.004) and progression-free (p=0.032) survival than glutaminase-low (RNA-Seq score<median) patients.
CONCLUSIONS: Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.

Keywords:  Immunotherapy; Pathology; Uterine Cancer

DOI:  https://doi.org/10.1136/ijgc-2024-005920
J Neurosci. 2025 Apr 14. pii: e0110252025. [Epub ahead of print]

Mitochondrial glutamine metabolism drives epileptogenesis in primary hippocampal neurons.

Helmut Kubista, Francesco Gentile, Klaus Schicker, Thomas Köcher, Stefan Boehm, Matej Hotka.

All available anti-seizure medications aim at symptomatic control of epilepsy, but there is no strategy to stop the development of the disease. The main reason is the lack of understanding of the epileptogenic mechanisms. Closing this knowledge gap is an essential prerequisite for developing disease-modifying therapies that can prevent the onset of epilepsy. Using primary co-cultures of hippocampal neurons and glial cells derived from rat pups of either sex, we show that epileptiform paroxysmal depolarization shifts (PDS) induce neuronal glucose hypometabolism which is compensated for by increased glutaminolysis. Glutaminolysis not only provides sufficient ATP to support electrical activity, but also leads to decreased vesicular glutamate release, thereby promoting neuronal hypersynchrony. Moreover, prolonged promotion of PDS increased neuronal arborization and synaptic density, which in combination with spontaneous recovery of neuronal glucose metabolism led to seizure-like discharge activity. Since inhibition of glutaminolysis did not prevent the PDS-induced morphogenesis, but eliminated seizure-like activity, we propose that glutaminolysis is a causative process linking neuronal metabolism with electrical activity thereby driving epileptogenesis.Significance statement The available pharmacotherapy for epilepsy provides symptomatic control of seizures by interfering with ictogenesis. However, understanding the preceding epileptogenic processes would offer an opportunity to intervene in the development of the disease. The electrical activity and glucose metabolism of the brain regions corresponding to the epileptic foci are disturbed long before the first seizures occur. The significance of the altered neuronal activity and metabolism is not well understood. We present evidence that abnormal neuronal electrical activity called paroxysmal depolarization shifts increase neuronal arborization and lead to metabolic shifts making neurons transiently rely on glutamine. We show that the interplay of these processes induces glucose hypometabolism, hyper-synchronization, and ultimately leads to seizure-like discharge activity, thus replicating several key features of epilepsy.

DOI: https://doi.org/10.1523/JNEUROSCI.0110-25.2025
Antioxid Redox Signal. 2025 Apr 16.

Impacts of Radiation on Metabolism and Vascular Cell Senescence.

Junichi Abe, Khanh Chau, Anahita Mojiri, Guangyu Wang, Masayoshi Oikawa, Venkata S K Samanthapudi, Abigail M Osborn, Keila C Ostos-Mendoza, Karla N Mariscal-Reyes, Tammay Mathur, Abhishek Jain, Joerg Herrmann, Syed Wamique Yusuf, Sunil Krishnan, Anita Deswal, Steven H Lin, Sivareddy Kotla, John P Cooke, Nhat-Tu Le.

  Significance: This review investigates how radiation therapy (RT) increases the risk of delayed cardiovascular disease (CVD) in cancer survivors. Understanding the mechanisms underlying radiation-induced CVD is essential for developing targeted therapies to mitigate these effects and improve long-term outcomes for patients with cancer. Recent Advances: Recent studies have primarily focused on metabolic alterations induced by irradiation in various cancer cell types. However, there remains a significant knowledge gap regarding the role of chronic metabolic alterations in normal cells, particularly vascular cells, in the progression of CVD after RT. Critical Issues: This review centers on RT-induced metabolic alterations in vascular cells and their contribution to senescence accumulation and chronic inflammation across the vasculature post-RT. We discuss key metabolic pathways, including glycolysis, the tricarboxylic acid cycle, lipid metabolism, glutamine metabolism, and redox metabolism (nicotinamide adenine dinucleotide/Nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADP+)/NADPH). We further explore the roles of regulatory proteins such as p53, adenosine monophosphate-activated protein kinase, and mammalian target of rapamycin in driving these metabolic dysregulations. The review emphasizes the impact of immune-vascular crosstalk mediated by the senescence-associated secretory phenotype, which perpetuates metabolic dysfunction, enhances chronic inflammation, drives senescence accumulation, and causes vascular damage, ultimately contributing to cardiovascular pathogenesis. Future Directions: Future research should prioritize identifying therapeutic targets within these metabolic pathways or the immune-vascular interactions influenced by RT. Correcting metabolic dysfunction and reducing chronic inflammation through targeted therapies could significantly improve cardiovascular outcomes in cancer survivors. Antioxid. Redox Signal. 00, 000-000.

Keywords:  aging; cardiovascular; inflammation; metabolism; microvascular; post-translational modifications; radiation therapy

DOI:  https://doi.org/10.1089/ars.2024.0741
FASEB J. 2025 Apr 30. 39(8): e70520

Metabolic Reprogramming of Glycolysis, Lipids, and Amino Acids in Tumors: Impact on CD8+ T Cell Function and Targeted Therapeutic Strategies.

Panping Liang, Zedong Li, Zhengwen Chen, Zehua Chen, Tao Jin, Fengjun He, Xiaolong Chen, Hongfeng Gou, Kun Yang.

  Tumor cells undergo metabolic reprogramming to support their rapid proliferation and to adapt to the challenges of the tumor microenvironment (TME). This involves significant changes in glycolysis, lipid, and amino acid metabolism, which not only promote tumor survival but also impact CD8+ T cells within the TME. This review examines how these metabolic alterations affect CD8+ T cell function, particularly through competition for energy resources and microenvironmental changes. For instance, aerobic glycolysis in tumor cells depletes glucose and leads to lactate accumulation, both of which suppress CD8+ T cell activity. Additionally, changes in lipid metabolism affect the composition of cell membranes and disrupt signal transduction, impairing T cell function. Amino acid reprogramming, such as increased consumption of glutamine and arginine by tumor cells, further hinders the activity and proliferation of CD8+ T cells. We also explore therapeutic strategies that target these metabolic pathways in tumor cells, such as inhibitors of glycolysis and fatty acid synthesis, which may enhance the antitumor activity of CD8+ T cells. These approaches show promise in improving both T cell function and the effectiveness of immune checkpoint blockade therapies. By investigating the link between tumor metabolism and CD8+ T cell dysfunction, this review highlights mechanisms of tumor immune evasion. This understanding can guide the development of novel immunotherapies aimed at enhancing T cell function within the TME.

Keywords:  CD8+ T cell; fatty acids; glutamine; glycolysis; metabolic reprogramming

DOI:  https://doi.org/10.1096/fj.202403019R
Nutrients. 2025 Mar 22. pii: 1113. [Epub ahead of print]17(7):

Emodin and Aloe-Emodin Reduce Cell Growth and Disrupt Metabolic Plasticity in Human Melanoma Cells.

Federica Baldassari, Marcella Bonanomi, Sara Mallia, Matteo Bonas, Elisa Brivio, Tecla Aramini, Danilo Porro, Daniela Gaglio.

  Background/Objectives: Melanoma is an aggressive skin cancer with intratumor metabolic heterogeneity, which drives its progression and therapy resistance. Natural anthraquinones, such as emodin and aloe-emodin, exhibit anti-cancer properties, but their effects on metabolic plasticity remain unclear. This study evaluated their impact on proliferation and metabolic pathways in heterogenous melanoma human cell lines. Methods: COLO 800, COLO 794, and A375 melanoma cell lines representing distinct metabolic phenotypes were analyzed. Targeted and untargeted metabolomics analyses integrated with Seahorse assays were performed to assess the effects of emodin and aloe-emodin on cell proliferation, mitochondrial function, and redox homeostasis. Glucose tracing using [U-13C6] glucose and metabolic flux analysis (MFA) were carried out to evaluate the glycolysis and TCA cycle dynamics. Results: Emodin and aloe-emodin inhibited proliferation by disrupting glycolysis, oxidative phosphorylation, and energy production across all cell lines. Both compounds impaired glucose metabolism, reduced TCA cycle intermediates, and induced mitochondrial ROS accumulation, causing oxidative stress and redox imbalance. Despite intrinsic metabolic differences, COLO 800 and COLO 794 upregulated antioxidant defenses; A375 enhanced one-carbon metabolism and amino acid pathways to maintain redox balance and nucleotide biosynthesis. Conclusions: Emodin and aloe-emodin can disrupt the metabolic plasticity of melanoma cells by impairing glycolysis, mitochondrial function, and redox homeostasis. Their ability to target metabolic vulnerabilities across diverse phenotypes highlights their therapeutic potential for overcoming resistance mechanisms and advancing melanoma treatment strategies.

Keywords:  anticancer drugs; biodiversity; melanoma; metabolic rewiring; metabolomics; natural compounds; phenotype shifting; treatment vulnerabilities

DOI:  https://doi.org/10.3390/nu17071113
Nat Cancer. 2025 Apr 18.

UnitedMet harnesses RNA-metabolite covariation to impute metabolite levels in clinical samples.

Amy X Xie, Wesley Tansey, Ed Reznik.

Comprehensively studying metabolism requires metabolite measurements. Such measurements, however, are often unavailable in large cohorts of tissue samples. To address this basic barrier, we propose a Bayesian framework ('UnitedMet') that leverages RNA-metabolite covariation to impute otherwise unmeasured metabolite levels from widely available transcriptomic data. UnitedMet is equally capable of imputing whole pool sizes and outcomes of isotope tracing experiments. We apply UnitedMet to investigate the metabolic impact of driver mutations in kidney cancer, identifying an association between BAP1 and a highly oxidative tumor phenotype. We similarly apply UnitedMet to determine that advanced kidney cancers upregulate oxidative phosphorylation relative to early-stage disease, that oxidative metabolism in kidney cancer is associated with inferior outcomes to anti-angiogenic therapy and that kidney cancer metastases demonstrate elevated oxidative phosphorylation. UnitedMet provides a scalable tool for assessing metabolic phenotypes when direct measurements are infeasible, facilitating unexplored avenues for metabolite-focused hypothesis generation.

DOI: https://doi.org/10.1038/s43018-025-00943-0
J Colloid Interface Sci. 2025 Apr 07. pii: S0021-9797(25)00936-1. [Epub ahead of print]692 137545

Tumor-microenvironment-driven carbon-center radical generation accompanied by glutathione exhaustion for intensified chemodynamic therapy.

Qian Lin, Yueyang He, Yang Li, Qiuyue Sun, Fu-Nan Li, Jinyan Lin, Xuan Zhu.

  The high redox levels within tumors position chemodynamic therapy (CDT) as a promising therapeutic approach. However, the CDT efficiency of dihydroartemisinin (DHA) is limited by rapid clearance from bloodstream, along with inadequate endogenous ferrous ions within tumor microenvironment and heightened anti-oxidative defense inside tumor cells. To overcome these limitations, we developed an innovative virus-like hollow mesoporous manganese nanocage, loaded with DHA and subsequently cloaked with red cell membrane, designed to trigger a tumor-microenvironment-responsive free radical generation, synergized with glutathione (GSH) exhaustion for enhanced CDT efficacy. Upon accumulation in tumor tissues via the enhanced penetration and retention (EPR) effect, the high concentration of GSH in cancer cells initiates the degradation of the nanocages. This process specifically and efficiently released both Mn2+ and DHA while simultaneously depleting GSH. The released Mn2+ further catalyzed the conversion of DHA to generate large amounts of highly toxic carbon-center (•C) radicals accompanied by the generation of Mn4+. The •C radical generation led to severe mitochondria dysfunction and DNA damage, potentially causing cancer cell death. The concurrently generated Mn4+ continued to depelete intracellular GSH and induce lipid peroxidation, thereby weakening cancer cells' anti-oxidative defenses and amplifing oxidative stress. The viability of 4T1 cells treated with DHA@vhmMN@RM was significantly lower (about 30 %) than other groups. This work presents a novel nanosystem that specifically enhances the therapeutic effect of CDT by leveraging a tumor microenvironment-responsive free radical generation, coupled with GSH exhaustion, offering a new avenue for targeted drug delivery and synergistic cancer therapy.

Keywords:  Carbon-center radical; GSH exhaustion; Hollow mesoporous manganese nanocages; Oxidative stress amplification; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jcis.2025.137545
BMC Med. 2025 Apr 14. 23(1): 217

The impact of metabolic reprogramming on tertiary lymphoid structure formation: enhancing cancer immunotherapy.

Meng-Jie Zhang, Yan Wen, Zhi-Jun Sun.

   BACKGROUND: Cancer immunotherapy has achieved unprecedented success in the field of cancer therapy. However, its potential is constrained by a low therapeutic response rate.
MAIN BODY: Tertiary lymphoid structure (TLS) plays a crucial role in antitumor immunity and is associated with a good prognosis. Metabolic reprogramming, as a hallmark of the tumor microenvironment, can influence tumor immunity and promote the formation of follicular helper T cells and germinal centers. However, many current studies focus on the correlation between metabolism and TLS formation factors, and there is insufficient direct evidence to suggest that metabolism drives TLS formation. This review provided a comprehensive summary of the relationship between metabolism and TLS formation, highlighting glucose metabolism, lipid metabolism, amino acid metabolism, and vitamin metabolism.
CONCLUSIONS: In the future, an in-depth exploration of how metabolism affects cell interactions and the role of microorganisms in TLS will significantly advance our understanding of metabolism-enhanced antitumor immunity.

Keywords:  Cancer immunotherapy; Germinal center B cell; Metabolic reprogramming; T follicular helper cell; Tertiary lymphoid structure

DOI:  https://doi.org/10.1186/s12916-025-04037-7
Trends Endocrinol Metab. 2025 Apr 16. pii: S1043-2760(25)00051-7. [Epub ahead of print]

Fumarate integrates metabolism and immunity in diseases.

Jie Cheng, Yifeng Xiao, Peng Jiang.

  Fumarate is a key metabolite produced primarily by the tricarboxylic acid (TCA) and urea cycles. In addition to having a metabolic role, its electrophilicity enables it to covalently modify cysteines; moreover, because of its α-ketoglutarate (α-KG)-like structure, it can also act as a competitive inhibitor of α-KG-dependent dioxygenases for epigenetic remodeling. Recent advances have broadened the role of fumarate as a bridge between metabolism and both innate and adaptive immunity, suggesting potentially important functions in anticancer immunity and autoimmune diseases. Here we review the connections between fumarate metabolism and immunity; we describe the mechanisms of fumarate regulation in cancer, autoimmunity, and other diseases; and we explore the clinical implications of fumarate and its esters for immunotherapy.

Keywords:  diseases; fumarate metabolism; immunity; succination

DOI:  https://doi.org/10.1016/j.tem.2025.03.008