bims-glucam 2026-09-06 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–09–06
nineteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine stress promotes metastatic potential via hexosamine biosynthetic pathway activity in KRAS/STK11-mutant lung adenocarcinoma.
Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration.
Efficacy of glutamine supplementation in postoperative patients undergoing hepatic surgery: a systematic review and meta-analysis of randomized controlled trials.
Correction: Hypoxia and aspirin additively increase intracellular glutamine accumulation in PIK3CA-mutated colorectal cancer cells.
YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer.
Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.
EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.
Targeting metabolic reprogramming in cancer: Past, present, and future.
Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.
Resistance-oriented immunometabolic circuits in laryngeal squamous cell carcinoma: glycolysis-lactate signaling, mitochondrial stress, and tumor-myeloid crosstalk.
The insulin-like growth factor 2 mRNA-binding protein 2 affects tumor cell metabolism via mitochondrial transporter activity and lipid alterations.
Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.
Glutaminase 1-mediated glutaminolysis regulates tuberculosis progression by modulating Th1 and Th17 immune responses.
Integration of histopathology and molecular features for the classification of benign and malignant hepatocellular neoplasms.
TRACE: An Integrated Isotope-Tracing Framework for Metabolite Validation and Nutrient Fate Mapping.
Targeting the PD-L1-induced PDK4/GLS metabolic axis overcomes anti-PD-1 resistance in non-small cell lung cancer.
Targeting glutaminase (GLS) to suppress CXCL8 secretion and sensitize esophageal squamous cell carcinoma to immunotherapy.
Autoimmune disease patients with comorbid cancer exhibit prominent immunometabolic crosstalk.
Immune licensing of exercise: B cells wire a liver-muscle glutamate axis.

Res Sq. 2026 Aug 27. pii: rs.3.rs-10670097. [Epub ahead of print]

Glutamine stress promotes metastatic potential via hexosamine biosynthetic pathway activity in KRAS/STK11-mutant lung adenocarcinoma.

Paula Deming, Shannon Prior, Cole Royer, Logan Sands, Melissa Scheiber, Sean Lenahan, Eyal Amiel, Allison Racela, David Seward.

Lung cancer is the leading cause of cancer-related deaths worldwide. Loss of STK11 in KRAS-driven lung adenocarcinoma (LUAD) is observed in approximately 15,000 US lung cancer cases annually and drives an aggressive, resistant disease. STK11 regulates many cellular processes, including metabolism, and loss of this tumor suppressor drives a "glutamine addicted" phenotype that is being considered for targeted therapy. However, recent work from our group revealed the activation of pro-oncogenic signaling in KRAS/STK11-mutant LUAD cells upon glutamine deprivation, suggesting the development of an advantageous adaptation. Here, we demonstrate that STK11 loss in KRAS-driven LUAD cells increases glutamine-dependent mitochondrial respiration, which is metabolically rewired upon exogenous glutamine deprivation to enhance the hexosamine biosynthetic pathway (HBP). Furthermore, our results reveal that enhanced HBP flux in STK11 null KRAS-driven LUAD cells promotes a pro-metastatic phenotype characterized by adherent cell detachment, resistance to apoptosis, and 3D spheroid invasion. This study highlights, for the first time, enhanced HBP flux as a protective shunt in response to glutamine deprivation in KRAS/STK11-mutant LUAD. Our results challenge the potential benefit of glutamine deprivation as a therapeutic intervention in this patient population. Future work aims to further elucidate the role of the HBP in promoting metastasis and to determine the mechanism(s) by which STK11 null KRAS-driven LUAD cells upregulate the HBP.

DOI: https://doi.org/10.21203/rs.3.rs-10670097/v1
Mol Biomed. 2026 Sep 01. pii: 155. [Epub ahead of print]7(1):

Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration.

Haoran Hu, Tao Han, Qiyuan Huang, Ping Gong, Jiangxi Liu, Hao Wang, Xiaowei Ling, Kang Wang, Shuangshuang Liu, Yue Yu, Ting Luo, Feng Cheng, Xiaoxiao Liu.

  The liver possesses an extraordinary capacity to regenerate after injury or surgical resection, a process highly dependent on the coordinated orchestration of the immune microenvironment. Although macrophages are recognized as pivotal coordinators of hepatic tissue repair, the precise checkpoints governing their functional transitions during regeneration remain elusive. Here, we identify the glutamine transporter SLC1A5 (Solute Carrier Family 1 Member 5) as a critical metabolic gatekeeper of macrophage function during liver regeneration. Using a mouse model of partial hepatectomy, we show that SLC1A5 is markedly upregulated in monocyte-derived macrophages at the peak of regeneration. Myeloid specific deletion of Slc1a5 (Slc1a5fl/flLyz2cre) severely impairs hepatocyte proliferation and diminishes the expression of macrophage derived regenerative factors. Mechanistically, Slc1a5 deficiency depletes intracellular glutamine, which triggers macrophage senescence and drives a pro-inflammatory phenotype. This senescent state selectively downregulates Gas6 (Growth Arrest Specific 6), a crucial bridging ligand for efferocytosis, thereby impairing apoptotic cell clearance and exacerbating local inflammation. Strikingly, exogenous Gas6, senolytic Quercetin therapy, or in vivo L-glutamine supplementation successfully alleviates macrophage senescence, reinstates Gas6 mediated efferocytosis, and rescues defective liver regeneration. Collectively, our findings reveal a novel 'Slc1a5-glutamine-senescence-efferocytosis' axis that dictates macrophage driven tissue repair. This study not only uncovers a fundamental immunometabolic mechanism but also highlights glutamine supplementation and senolytics therapy as promising clinically strategies to accelerate liver regeneration.

Keywords:  Cell senescence; Efferocytosis; Liver regeneration; Macrophage; SLC1A5

DOI:  https://doi.org/10.1186/s43556-026-00526-0
Clinics (Sao Paulo). 2026 Sep 01. pii: S1807-5932(26)00213-9. [Epub ahead of print]81 101086

Efficacy of glutamine supplementation in postoperative patients undergoing hepatic surgery: a systematic review and meta-analysis of randomized controlled trials.

Xuezheng Meng, Mingming Zhang, Xinran Wang.

   BACKGROUND: The efficacy and safety of glutamine supplementation in patients receiving hepatic surgery remain controversial.
METHODS: A search strategy incorporating the terms "glutamine", "liver transplantation", and "hepatectomy" was applied across eight literature databases. Study quality was evaluated via the Risk of Bias 2.0 (ROB 2.0) tool, while statistical analyses were undertaken through R 4.4.1.
RESULTS: 18 studies involving 1198 patients were encompassed. Meta-analysis revealed that immune factors Immunoglobulin A (IgA), Immunoglobulin M (IgM), Cluster of Differentiation 3 (CD3), Cluster of Differentiation 4 (CD4), and CD4/Cluster of Differentiation 8 (CD8) were significantly higher in the glutamine cohort than those in the control cohort(SMD = 1.21, 0.25, 1.52, 0.99, and 0.77). Levels of inflammatory markers C-Reactive Protein (CRP), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Interleukin-8 (IL-8) were markedly lower in the glutamine group (SMD = -2.03, -3.29, -1.86, -2.20, and -2.29). The glutamine cohort also exhibited a significant decrease in liver function indicators Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) (SMD = -1.03 and -1.05), while Cholinesterase (CHE) levels were significantly elevated (SMD = 0.61). Serum protein levels, including Albumin (ALB), Prealbumin (PA), and Total Protein (TP), were significantly higher in patients receiving glutamine (SMD = 0.68, 1.09, and 0.81). In addition, Adverse Events (AEs), defined as overall postoperative complications, were significantly less frequent in the glutamine group (RR = 0.59, 95% CI 0.44‒0.79).
CONCLUSION: Glutamine supplementation in postoperative hepatic surgery patients enhances immune function, reduces inflammation, improves liver function, and decreases the incidence of AEs.

Keywords:  Glutamine; Hepatectomy; Liver transplantation; Meta-analysis; Systematic review

DOI:  https://doi.org/10.1016/j.clinsp.2026.101086
Sci Rep. 2026 Aug 31. pii: 27279. [Epub ahead of print]16(1):

Correction: Hypoxia and aspirin additively increase intracellular glutamine accumulation in PIK3CA-mutated colorectal cancer cells.

Nodoka Umezaki, Shogen Boku, Yoshiyuki Matsuo, Tetsushi Yamamoto, Hironaga Satake, Motoki Watanabe, Kiichi Hirota, Tomoharu Sugie, Mitsugu Sekimoto.

DOI: https://doi.org/10.1038/s41598-026-65164-6
Adv Sci (Weinh). 2026 Aug 30. e77492

YTHDC1 Orchestrates Glucose and Glutamate Rewiring to Overcome Lethal Metabolic Stress in Triple-Negative Breast Cancer.

Zheng-Hao Lai, Yi Wang, Na-Na Li, Ling Zeng, Renzhong Liu, Xue Li, Cheukfai Li, Xin-Yu Ma, Wenkui Fu, Yingsen Tang, Jinjin Chen, Ning Liao, Man-Li Luo.

  Developing effective therapies for triple-negative breast cancer (TNBC) requires the identification of key molecular regulators. Here, among the major m6A modulators, we find that only the reader YTHDC1 is specifically overexpressed in TNBC and correlates to unfavorable prognosis. Mechanistically, YTHDC1 orchestrates glucose and glutamine metabolism in an m6A-dependent manner to confer robust adaptability to lethal metabolic stress in TNBC cells. It not only stabilizes GLUT3 mRNA to sustain glucose uptake and NADPH production, but also reduces the mRNA stability of ATF4, thereby suppressing the overexpression of the cystine/glutamate antiporter SLC7A11 to prevent excessive cystine uptake and glutamate export. YTHDC1 knockdown simultaneously disrupts glucose metabolism and upregulates SLC7A11, triggering disulfidptosis in TNBC cells in vitro and in vivo. Leveraging this YTHDC1 knockdown-induced metabolic vulnerability, we develop an ATF4 mRNA-targeted nanotherapy, which delivers mRNA directly to the cytoplasm and bypasses m6A-mediated destabilization by YTHDC1 in the nucleus. By promoting SLC7A11 expression, therapeutic overexpression of ATF4 sensitizes TNBC cells to disulfidptosis upon GLUT inhibitor BAY-876 treatment, and to glutamate deprivation-induced cell death upon GLS inhibitor CB-839 treatment. Collectively, this work reveals YTHDC1 as a pivotal coordinator of the glucose-glutamine-cystine metabolic network and provides ATF4 mRNA nanomedicine-based combination strategies to improve TNBC therapeutic efficacy.

Keywords:  YTHDC1; disulfidptosis; m6A; metabolism; triple‐negative breast cancer

DOI:  https://doi.org/10.1002/advs.77492
Food Res Int. 2026 Oct 31. pii: S0963-9969(26)01722-9. [Epub ahead of print]242(Pt 3): 120038

Opposite metabolic and gut responses to oral glutamine in male and female mice with diet-induced obesity.

Candice Lefebvre, Adam Tiffay, Charles-Edward Breemeersch, Virginie Dreux, Christine Bôle-Feysot, Charlène Guérin, Jonathan Breton, Elise Maximin, Magali Monnoye, Pierre Déchelotte, Véronique Douard, Moïse Coëffier, Alexis Goichon.

  Obesity is often associated with sex-dependent metabolic complications, to which altered intestinal barrier function and gut microbiota contribute. Glutamine supplementation has previously shown beneficial effects on gut barrier function and glycemic control. We thus aimed to characterize, in male and female mice, the effects of oral glutamine supplementation during high-fat-diet-induced obesity. Male and female C57BL/6 mice received a standard (SD) or high-fat diet (HFD; 60 % kcal from fat) for 14 weeks (W14). From W12 onward, mice received glutamine in drinking water (2 g/kg/day) or no supplementation. Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic inflammatory response, cecal microbiota and inflammatory/endocrine adipose response were assessed. In both male and female mice, glutamine supplementation failed to improve body weight and body composition. However, glutamine reduced glucose intolerance in HFD-fed males (AUC reduced by 14.57 %) that was associated with a partial restoration of plasma resistin and insulin and a trend toward limiting adipose inflammatory response. In males, glutamine did not affect gut microbiota composition and colonic response. Conversely, in HFD-fed females, glutamine supplementation led to gut microbiota changes (increase in Bacteroidota and Pseudomonadota phyla; increase in Muribaculaceae and Tannerellaceae families), increased colonic inflammatory markers (Il1b, Tlr4, Myd88, Irf3), increased inflammatory response in subcutaneous adipose tissue and increased HOMA-IR. Finally, HFD-fed mice exhibited sex-specific responses to glutamine supplementation with protective effects in males and harmful effects in females that need to be further deeply explored.

Keywords:  Glutamine; Gut; Microbiota; Obesity; Sex

DOI:  https://doi.org/10.1016/j.foodres.2026.120038
Exp Neurol. 2026 Aug 29. pii: S0014-4886(26)00366-3. [Epub ahead of print]407 116000

EAAT1 sustains redox homeostasis and temozolomide resistance through glutamate-dependent regulation of the Keap1/Nrf2 axis in glioblastoma.

Lufei Chen, Ruying Lin, Yongpei Xu, Shiqi Lin, Jinyuan Fan, Huiyao Zhang, Ying Zhou, Qinyong Ye, Zucheng Ye.

  Glioblastoma (GBM) exhibits profound metabolic and redox adaptation that supports tumor progression and therapeutic resistance. Here, we identify the glutamate transporter EAAT1 (SLC1A3) as a critical regulator of glutamate-dependent redox homeostasis in GBM. Analysis of TCGA, GTEx, and CGGA datasets showed that EAAT1 expression is elevated in GBM and that higher EAAT1 expression is associated with poor patient survival. Using CRISPR/Cas9-mediated EAAT1 knockout together with biochemical, imaging, transcriptomic, and in vivo approaches, we found that loss of EAAT1 altered extracellular and intracellular glutamate homeostasis, reduced intracellular glutamate, glutamine, and glutathione levels, and increased reactive oxygen species (ROS) accumulation. EAAT1 deficiency also suppressed oxidative phosphorylation and ROS-related programs and attenuated the Keap1/Nrf2/HO-1 antioxidant axis, accompanied by reduced GPX4 expression and increased lipid peroxidation. Furthermore, EAAT1 ablation downregulated glutamine synthetase and glutaminase, suggesting impaired glutamine-dependent anaplerotic metabolism. Glutamate supplementation partially restored Keap1/Nrf2/HO-1 pathway protein expression in EAAT1-knockout cells. Functionally, EAAT1 loss inhibited GBM cell proliferation and migration, enhanced sensitivity to oxidative stress and temozolomide (TMZ), and reduced tumor growth in xenograft models. Collectively, our findings establish EAAT1 as a key metabolic regulator linking glutamate transport to antioxidant defense and therapeutic response in GBM. Targeting EAAT1 may therefore represent a metabolic vulnerability for overcoming metabolic and redox adaptation and improving TMZ responsiveness in GBM.

Keywords:  EAAT1; Glioblastoma; Glutamate; Oxidative stress

DOI:  https://doi.org/10.1016/j.expneurol.2026.116000
Pharmacol Ther. 2026 Aug 29. pii: S0163-7258(26)00136-1. [Epub ahead of print]288 109109

Targeting metabolic reprogramming in cancer: Past, present, and future.

Niti Kumari, Surendra K Shukla, Ravi Thakur.

  Cancer cells undergo profound metabolic reprogramming to sustain uncontrolled proliferation within a nutrient-limited and often hypoxic tumor microenvironment (TME). Metabolic rewiring is an active driver of oncogenesis, immune evasion, epigenetic remodeling, and therapy resistance. Over the past century, our understanding of tumor metabolism has grown from Warburg's seminal description of aerobic glycolysis to a comprehensive adaptive network. Cancer cells coordinate glucose catabolism, mitochondrial oxidative metabolism, fatty acid synthesis and oxidation, amino acid catabolism, nucleotide biosynthesis, and one‑carbon metabolism into an integrated metabolic framework. These pathways form a deeply interconnected web in which metabolic intermediates serve as biosynthetic building blocks, bioenergetic substrates, redox buffers, signaling molecules, and epigenetic cofactors. Within the TME, metabolic competition between tumor cells and immune cells, together with the accumulation of immunosuppressive metabolites such as lactate, kynurenine, and adenosine, creates a profoundly immune-hostile landscape. Recent work has further revealed that key post-translational modifications, directly driven by metabolic flux, reshape the chromatin and proteome of both cancer cells and tumor-infiltrating immune cells, linking metabolism to gene regulation in previously unanticipated ways. Therapeutically, the FDA approval of IDH1/IDH2 inhibitors for acute myeloid leukemia demonstrated that metabolic enzymes are tractable oncology drug targets. Yet the broader effort to translate metabolic insights into robust clinical benefit has encountered formidable obstacles, including metabolic plasticity, intratumoral heterogeneity, overlap with normal tissue function, and inadequate biomarkers. This review traces the evolution of our understanding of cancer metabolism from its origins to therapeutic targeting. It further examines how anabolic and catabolic pathways, energy production, redox balance, and metabolic crosstalk across intracellular, intercellular, and systemic domains shape tumor biology and therapeutic response. It also critically analyzes approved and investigational metabolic therapies and charts a course for the emerging era of precision metabolic oncology.

Keywords:  Cancer metabolism; Epigenetics; Ferroptosis; Glycolysis; Immunometabolism; Metabolic reprogramming; Oncometabolites; Oxidative phosphorylation; Tumor microenvironment; Warburg effect

DOI:  https://doi.org/10.1016/j.pharmthera.2026.109109
Cancer Discov. 2026 Sep 01. 16(9): 1727-1729

Mitochondrial Complex I at the Crossroads of NK cell Dysfunction in Glioblastoma.

Silvia Tiberti, Katayoun Rezvani, May Daher.

Zhou and colleagues identify mitochondrial complex I activity, mediated through NDUFA9, as a critical determinant of natural killer (NK) cell metabolic fitness and antitumor function in glioblastoma. Their study links impaired oxidative phosphorylation to glutamine dependence, epigenetic repression of effector programs, and loss of NK cell activity, highlighting mitochondrial fitness as an actionable axis for improving cellular immunotherapy in solid tumors. See related article by Zhou et al., p. 1924.

DOI: https://doi.org/10.1158/2159-8290.CD-26-1267
Front Immunol. 2026 ;17 1907469

Resistance-oriented immunometabolic circuits in laryngeal squamous cell carcinoma: glycolysis-lactate signaling, mitochondrial stress, and tumor-myeloid crosstalk.

Jingjing Sun, Yongxiang Zou, Huimin Yang, Hui Li.

  Laryngeal squamous cell carcinoma (LSCC) remains clinically challenging because of immune escape and resistance to chemotherapy, radiotherapy, and immune checkpoint blockade. Although immunometabolism encompasses diverse nutrient, redox, and stromal pathways, LSCC-specific evidence is currently strongest for glycolysis/lactate metabolism, mitochondrial remodeling, oxidative stress adaptation, ferroptosis-related regulation, extracellular-vesicle-mediated macrophage remodeling, and checkpoint-associated T-cell dysfunction. This focused review therefore examines resistance-oriented immunometabolic circuits rather than providing an exhaustive catalogue of all metabolic pathways. We discuss how glycolytic activation and lactate accumulation may generate nutrient-competitive and acidic niches; how mitochondrial stress, ROS adaptation, and ferroptosis-related processes influence tumor survival; and how tumor-derived vesicles, TAMs, TILs, Tregs, pDCs, and emerging neutrophil/CAF-related signals shape immune escape. Underexplored axes, including lipid and amino-acid metabolism, glutamine dependence, arginine metabolism, tryptophan-IDO signaling, adenosine metabolism, hypoxia/HIF signaling, NK cells, MDSCs, endothelial cells, and broader stromal-immune interactions, are highlighted as evidence gaps requiring LSCC-specific validation. This review proposes a focused framework for biomarker development and rational combination therapy.

Keywords:  glycolysis–lactate axis; laryngeal squamous cell carcinoma; mitochondrial stress; therapeutic resistance; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2026.1907469
Cell Death Discov. 2026 Sep 01. pii: 353. [Epub ahead of print]12(1):

The insulin-like growth factor 2 mRNA-binding protein 2 affects tumor cell metabolism via mitochondrial transporter activity and lipid alterations.

Sandra Kendzia, Susanne Franke, Marcello Pirritano, Eva Grafahrend-Belau, Nikolai Köhler, Theresa Bauchspiess, Sören Franzenburg, Marcus Höring, Elia Raab, Linus Schmeier, Sinem Sürmeli, Frank Erdmann, Johannes Klose, Jörg Kleeff, Michael Boettcher, Gerhard Liebisch, Josch K Pauling, Martin Simon, Björn H Junker, Sonja M Kessler.

The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family is overexpressed in cancer and associated with poor prognosis. IGF2BP2 has been linked to single metabolic alterations by acting on its RNA targets. Here, we used a comprehensive approach to elucidate the effects of IGF2BP2 on primary and lipid metabolism. 13C-metabolic flux analysis (MFA) combined with RNA-Seq data revealed that IGF2BP2 affects mitochondrial fluxes by regulating the expression of several mitochondrial transporters, such as mitochondrial pyruvate carrier 1 (MPC1) and uncoupling protein 2 (UCP2). Methyl pyruvate reversed the gene expression patterns of UCP2 and CPT1A in HCT116 IGF2BP2 knockout (KO) cells by bypassing MPC1. Interestingly, an altered expression of the transporter UCP2 was also observed in a patient-derived tumor organoid (PDO), in which IGF2BP2 was knocked down. The altered glutamine metabolism seen in the 13C-MFA and the citrate label data derived from extracted mitochondria confirm a rerouting of glutamine almost exclusively into the mitochondria and a reduction of glycolytic carbon intake into the mitochondria. Due to changes in palmitate labeling patterns, lipid stainings were performed, suggesting lipid accumulation in KO cells. A lipidomic analysis revealed altered compositions across almost all lipid species. Further, lipogenic genes involved in fatty acid and cholesterol metabolism were differentially expressed. Most of the differentially expressed genes are potential direct targets of IGF2BP2 based on publicly available IGF2BP2 CLIP data. Overall, these results show the influence of IGF2BP2 on the central carbon metabolism of cancer cells, primarily through its effects on MPC1 and the resulting effects on UCP2. The complex interaction of IGF2BP2 with the metabolic network provides important insights into tumor metabolism, particularly relevant to tumor growth and resistance to therapy.

DOI: https://doi.org/10.1038/s41420-026-03315-4
Front Immunol. 2026 ;17 1894113

Human CD4+ iNKT cells have highly oxidative metabolism and use glycogen reserves to sustain IFN-γ production in nutrient-limited environments.

Niharika M Patankar, Kelsey A Smith, Nidus Jacobsen, Nikhila S Bharadwaj, Jenny E Gumperz.

  Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cellular immunotherapy, but the metabolic pathways that support their effector function in nutrient-limited tumor microenvironments remain poorly defined. Human iNKT cells segregate into CD4+ and CD4⁻CD8⁻ double-negative (DN) subsets with distinct functional profiles, yet whether they use divergent metabolic strategies to sustain IFN-γ production is unknown. Here we show that in vitro-expanded human CD4+ and DN iNKT cells employ distinct metabolic programs that differentially support IFN-γ secretion under nutrient stress. DN iNKT cells exhibit higher Glut1 expression and a more glycolytic phenotype, with IFN-γ production that is sensitive to extracellular glucose withdrawal and glycolytic inhibition. In contrast, CD4+ iNKT cells display high spare respiratory capacity, preferentially engage glutamine-supported mitochondrial respiration, and maintain IFN-γ production despite glucose deprivation or 2-DG inhibitor treatment. CD4+ iNKT cells generated excess ATP through oxidative metabolism, accumulated intracellular glycogen stores during expansion in vitro, and subsequently mobilized this glycogen to support IFN-γ production in tumor-exhausted media. Using a xenograft model of EBV-driven B cell lymphoma, we show that adoptively transferred human CD4+ iNKT cells infiltrate tumors in vivo and are associated with elevated intratumoral IFN-γ. These findings identify a distinctive combination of high mitochondrial oxidative capacity, glutamine utilization, and glycogen storage that endows human CD4+ iNKT cells with exceptional metabolic resilience, suggesting that CD4+ iNKT-based products may provide a particularly valuable platform for adoptive cellular immunotherapy.

Keywords:  glucose independence; glycogen stores; interferon-gamma (IFN-g); invariant natural killer T (iNKT) cell; metabolic resilience; oxidative phosphorylation (OXPHOS); spare respiratory capacity (SRC)

DOI:  https://doi.org/10.3389/fimmu.2026.1894113
Cent Eur J Immunol. 2026 ;51(2): 121-132

Glutaminase 1-mediated glutaminolysis regulates tuberculosis progression by modulating Th1 and Th17 immune responses.

Xiaozhen Cai, Yidan Huang, Lili Zeng, Rong Rong.

   Introduction: Mycobacterium tuberculosis-mediated tuberculosis (TB) is an infectious disease that results in approximately 1.2 million deaths annually. Glutaminase (GLS1) is a metabolic enzyme involved in glutaminolysis. The current study examined the roles and mechanisms of GLS1 in TB progression.
Material and methods: Peripheral blood mononuclear cells (PBMCs) were extracted from TB patients and healthy individuals, and CD4+ T and CD14+ monocytes were sorted. PBMCs were incubated with M. tuberculosis strain H37Rv lysate to stimulate immune responses and treated with BPTES, a GLS1 inhibitor. RT-qPCR and western blotting were employed to detect mRNA and protein levels, respectively. Immunophenotyping of cells was performed using flow cytometry. ELISA was used to determine cytokine levels. Colony-forming unit assays were used to evaluate M. tuberculosis survival in macrophages. ChIP assays were used to detect the enrichment of H3K9ac/H3K27ac at the gene promoters.
Results: GLS1 was elevated in CD4+ T cells from TB patients and H37Rv lysate-stimulated PBMCs. GLS1-mediated glutaminolysis promoted Th1 and Th17 cell differentiation. Inhibition of GLS1 by BPTES facilitated M. tuberculosis survival in macrophages. GLS1 inhibition reduced H3K9ac and H3K27ac epigenetic modification in the promoter region of interferon γ and interleukin 17.
Conclusions: GLS1-mediated glutaminolysis may regulate TB progression by modulating Th1 and Th17 immune responses via epigenetic regulation.

Keywords:  GLS1; Th1; Th17 immune response; glutaminolysis; tuberculosis

DOI:  https://doi.org/10.5114/ceji/208684
Virchows Arch. 2026 Sep 01.

Integration of histopathology and molecular features for the classification of benign and malignant hepatocellular neoplasms.

Christine Sempoux, Young Nyun Park.

  The diagnostic of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC) has shifted from a classical morphological evaluation to a complex and precise morpho-molecular analysis that represents a core focus of the updated 6th edition of the WHO classification of digestive system tumours. Four molecular pathways across five distinct subtypes have been identified for HCA, with clinical implications. When specific immunohistochemical and molecular techniques are applied, less than 5% of HCAs remain unclassified. At least 39% of progressed HCCs display unique morpho-molecular characteristics spanning nine distinct subtypes, while the remainder is classified as conventional HCC (cHCC). These subtypes encompass categories with a poor prognosis (macrotrabecular-massive, neutrophil-rich, and sarcomatoid), a favorable prognosis (lymphocyte-rich and clear cell), a variable prognosis (scirrhous), and a prognosis similar to cHCC (steatohepatitic, chromophobe, and fibrolamellar). Recently, two novel histological patterns have been introduced: the vessels encapsulating tumour clusters pattern and the CTNNB1-mutated pattern. Moreover, keratin 19 remains a well-established immunohistochemical marker strongly associated with a poor prognosis. Together, these advancements underscore the critical need to integrate molecular and histological data to optimize patient stratification and therapeutic outcomes.

Keywords:  Glutamine synthetase; Hepatocellular adenoma; Hepatocellular carcinoma; Keratin 19; Macrotrabecular massive; Vessels encapsulating tumour clusters

DOI:  https://doi.org/10.1007/s00428-026-04685-x
Anal Chem. 2026 Sep 01. 98(34): 24964-24975

TRACE: An Integrated Isotope-Tracing Framework for Metabolite Validation and Nutrient Fate Mapping.

Rui Li, Junyao Wang, Yuanhong Shan, Zuohan Xie, Yuzhe Xiao, Weidong Zhuang, Yongzhen Tao, Jinyu Zhou, Lifeng Yang, Lin Wang.

Untargeted LC-MS metabolomics offers a broad view of the microbial metabolism. However, its application is hindered by two intertwined challenges: distinguishing true biological signals from chemical artifacts and quantifying nutrient partitioning under nutrient-competitive conditions. Here, we present TRACE, an integrated experimental and computational framework that dynamically calibrates mass and retention time tolerances from the data itself to construct isotope-informed peak networks, enabling rigorous discrimination of biological metabolites from artifacts. Across four LC-MS platforms, TRACE reveals that the proportion of high-confidence annotations fell from 2.94 to 1.48%, while the total features increased by 331% from lower- to higher-sensitivity instruments. TRACE also maps nutrient fates into metabolic pathways by detecting isotopic dilution in Saccharomyces cerevisiae cultured with 13C-glucose, 15N-ammonium, and other unlabeled nutrients. Specifically, labeling of glutathione, a linear assembly of three amino acids, accurately reflect direct incorporation from its constituent amino acids; NAD+, whose biosynthesis proceeds through concurrent salvage and de novo pathways, revealed how adenine, tryptophan, and glutamine shaped its final isotopologue pattern. By converting untargeted LC-MS data into functional maps of nutrient flow, TRACE establishes a system-level approach to interrogate microbial metabolism under physiologically relevant competitive conditions.

DOI: https://doi.org/10.1021/acs.analchem.6c02292
J Immunother Cancer. 2026 Sep 02. pii: e015037. [Epub ahead of print]14(9):

Targeting the PD-L1-induced PDK4/GLS metabolic axis overcomes anti-PD-1 resistance in non-small cell lung cancer.

Wenxin Lian, Hui Yang, Yuqi Zhang, Chenchen Liu, Chunyao Fang, Mengyue Xu, Yixing Yang, Yan Wang, Runqiu Jiang, Jing Xu, Wen Gao.

   BACKGROUND: Metabolic reprogramming within the tumor microenvironment is a pivotal barrier to effective immune checkpoint blockade (ICB). While programmed death ligand 1 (PD-L1) is well characterized as a ligand inhibiting T-cell function, its intrinsic 'reverse signaling' role in regulating tumor metabolism and shaping the immune landscape remains poorly understood. Here, we investigated the metabolic determinants of resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy and the underlying molecular mechanisms.
METHODS: Integrated metabolomics and transcriptomics were performed on tumor samples from patients with non-small cell lung cancer and cell lines. Mechanisms were delineated using RNA sequencing, cleavage under targets and tagmentation assays, metabolic flux analysis, and coculture systems. The therapeutic efficacy of targeting metabolic effectors was evaluated in syngeneic mouse models and correlated with immune profiling.
RESULTS: We identified a distinct metabolic signature characterized by aberrant pyruvate accumulation in patients resistant to anti-PD-1 therapy. Mechanistically, we demonstrate that antibody-mediated ligation of PD-L1 triggers an intrinsic endoplasmic reticulum (ER) stress response via the PERK-ATF4-CHOP axis. ATF4 acts as a transcriptional activator that directly upregulates pyruvate dehydrogenase kinase 4 (PDK4) (blocking pyruvate oxidation) and glutaminase (GLS) (promoting glutaminolysis), creating a 'dual-hit' metabolic rewiring that drives intracellular pyruvate build-up. Subsequently, tumor-secreted pyruvate is taken up by tumor-associated macrophages (TAMs) via MCT1, inducing mitochondrial reactive oxygen species accumulation and driving them into a state of cellular senescence. These senescent TAMs upregulate PD-L1 via STAT3 signaling, thereby reinforcing an immunosuppressive feedback loop. Pharmacological inhibition of PDK4 and GLS effectively abolished pyruvate accumulation, prevented macrophage senescence, and restored CD8+ T-cell cytotoxicity.
CONCLUSIONS: Our study identifies a novel 'PD-L1-ER stress-pyruvate-macrophage senescence' axis as a key mechanism underlying primary resistance to ICB. These findings highlight the non-canonical reverse-signaling function of PD-L1 in metabolic remodeling and propose that targeting the PDK4/GLS-dependent pyruvate surge offers a promising therapeutic strategy to sensitize tumors to anti-PD-1 immunotherapy.

Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Lung Cancer; Macrophage; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-015037
J Chemother. 2026 Sep 01. 1-17

Targeting glutaminase (GLS) to suppress CXCL8 secretion and sensitize esophageal squamous cell carcinoma to immunotherapy.

Xiu Zhang, Jiang Chao, Zhuqing Ji, Kai Chen.

  Immune checkpoint inhibitor (ICI) resistance remains a major challenge in esophageal squamous cell carcinoma (ESCC). This study investigates the role of glutaminase (GLS) in modulating the tumor immune microenvironment and its impact on immunotherapy response. Bioinformatic analysis of TCGA data revealed an inverse correlation between GLS expression and CD8+ T cell infiltration. In ESCC clinical specimens, high GLS expression correlated with elevated CXCL8 levels and reduced CD8+ T cell infiltration. Mechanistically, our data support an association between GLS expression and increased CXCL8 transcription, accompanied, at least in part, by HAT-dependent enhancement of H3K27 acetylation at the CXCL8 promoter region. In advanced ESCC patients receiving immunochemotherapy, high tumoral GLS expression was associated with significantly shorter progression-free survival. In vitro and in vivo functional studies showed that GLS knockdown in ESCC cells was associated with enhanced T-cell effector cytokine secretion, increased tumor infiltration of CD8+ T cells, and greater tumor suppression when combined with anti-PD-1 therapy in a humanized mouse model. Importantly, exogenous CXCL8 supplementation partially reversed the increased Granzyme B and IFNγ secretion induced by GLS knockdown in the co-culture system, supporting a functional role for CXCL8 in GLS-associated immune suppression. These results support a model in which GLS contributes to an immunosuppressive microenvironment in ESCC, at least in part through epigenetic upregulation of CXCL8. These findings support further investigation of GLS targeting as a potential strategy to improve immunotherapy response in ESCC.

Keywords:  CD8+ T-cell infiltration; CXCL8/IL-8; Glutaminase (GLS); combination therapy; immunotherapy resistance

DOI:  https://doi.org/10.1080/1120009X.2026.2722740
Sci China Life Sci. 2026 Aug 26.

Autoimmune disease patients with comorbid cancer exhibit prominent immunometabolic crosstalk.

Xu Jiang, Yangzhige He, Naixin Liang, Xiangyi Shen, Ziyue Zhou, Dan Yang, Jiana Chen, Jiaqi Xu, Mengyuan Wang, Yiyi Gong, Xiaoyan Si, Li Zhang, Lidan Zhao, Yunyun Fei, Fengchun Zhang, Mengtao Li, Huaxia Yang.

  Patients with autoimmune diseases (AIDs) are at an increased risk of developing cancer; however, the immunometabolic programs that shape this comorbidity remain incompletely defined. We integrated targeted serum metabolomics with multiplex profiling of cytokines, chemokines, and immune checkpoint proteins in patients with five major AIDs-idiopathic inflammatory myopathies, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis-with or without cancer. A total of 49 patients with AID and comorbid cancer (AID-CA), 47 patients with AID alone, and 15 healthy controls were enrolled. Compared with AID alone, AID-CA was associated with coordinated remodeling of amino acid and nucleotide metabolism, dominated by the alanine, aspartate, and glutamate pathways. Decreased L-glutamine and increased L-glutamic acid levels were consistently observed and remained significant after the false discovery rate correction. Immune profiling revealed modest but consistent differences, including higher levels of CXCL9 and Galectin-9 and lower levels of selected checkpoint molecules in AID-CA. The effects of major metabolites and immune mediators were directionally stable after adjusting for age, sex, treatment exposure, and autoimmune disease subtype. Integrative analyses revealed stronger associations between metabolites and immune mediators in AID-CA, centered on CXCL9 and Galectin-9, and linked to amino acid and pyrimidine metabolism. In ex vivo assays, perturbation of glutamine or arginine availability preferentially modulated the release of CXCL9 and Galectin-9 from peripheral blood mononuclear cells of patients with AID-CA. Together, these findings define an internally consistent immunometabolic pattern associated with cancer comorbidities in patients with AIDs. They nominated amino acid metabolism and CXCL9/Galectin-9-centered immune signaling as candidates for mechanistic investigation and biomarker development, while underscoring the need for validation in larger, longitudinal, and disease-specific cohorts.

Keywords:  autoimmune diseases; cancer comorbidity; immune profiling; immunometabolic crosstalk; metabolomics

DOI:  https://doi.org/10.1007/s11427-026-3465-2
J Mol Cell Biol. 2026 Sep 01. pii: mjag036. [Epub ahead of print]

Immune licensing of exercise: B cells wire a liver-muscle glutamate axis.

Yiqi Yu, Rong Rong, Weiwei Dai.

DOI: https://doi.org/10.1093/jmcb/mjag036