bims-glucam 2026-08-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–08–02
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.
Integrated Metabolomic and Transcriptomic Analyses Reveal that Glutamine Promotes Chicken PGCLC Specification Potentially through α-Ketoglutarate.
Glutamine Metabolism Supports α cell Mass and Glucagon Secretion.
Application of glutamine metabolism-related gene signatures in the non-invasive diagnosis of coronary artery disease: integrating bulk and single-cell transcriptomics.
NMN alleviates oxidative stress damage in alopecia areata by activating SIRT7 and promoting glutamine metabolism.
Real-time NMR analysis of glutamine metabolism for screening anti-cancer agents in living cells.
Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming.
HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.
Nrf2 Activation Alleviates Silica-Induced Toxicity in Alveolar Macrophages via Glutamine Metabolic Reprogramming.
Metabolic Reprogramming in Oral Cancer: A Narrative Review of Therapeutic Perspectives with Emphasis on Dichloroacetate.
Amino Acid and Lipid Metabolism in Cancer: Mechanisms and Therapeutic Opportunities.
Microenvironment-Driven Reprogramming in Colorectal Cancer Liver Metastasis: Metabolic, Phenotypic, and Immune Adaptation.
The Preventive Effect of Introducing Glutamine on Chemotherapy-Induced Diarrhea in Colorectal Cancer and Its Influence on Inflammatory Factors Such as CRP and IL-6.
Dysregulated myelopoiesis and enhanced glutaminase-dependent neutrophil survival in preclinical obesity.
Perioperative Immunonutrition in Patients Undergoing Lung Cancer Surgery: Current Evidence and Future Perspectives.

Pharmaceutics. 2026 Jul 13. pii: 850. [Epub ahead of print]18(7):

70 Years of DON and Beyond: Glutaminase Inhibition as a Synergistic Strategy in Cancer Combination Therapy.

José A Campos-Sandoval, Juan De Los Santos-Jiménez, Javier Márquez, José M Matés.

  Personalized oncology seeks to selectively block specific dysregulated pathways to arrest cancer development. Increased glutamine metabolism is a hallmark of cancer, and 6-diazo-5-oxo-L-norleucine (DON), a structural analog of L-glutamine, was the first compound used to target the exacerbated nitrogen metabolism observed in cancer cells. However, its clinical application was limited by unacceptable toxicity. With the same goal of blocking glutamine metabolism, several specific glutaminase inhibitors have been characterized in recent decades, showing promising antitumor activity. Nevertheless, this strategy frequently induces adaptive metabolic resistance that must be counteracted. In this context, glutaminase has become a key target in combination therapies for several tumor types aimed at restricting anabolic adaptation when single metabolic therapy fails, emerging as a possible synergistic therapeutic intervention. Consequently, combination therapies that include glutaminase inhibition alongside additional agents to counteract the metabolic plasticity of cancer have emerged as a promising approach in personalized antitumor pharmacology. This review provides a historical-to-translational overview of glutamine-targeted therapies, with particular emphasis on glutaminase inhibitors, including compound 968, BPTES, CB-839, and next-generation inhibitors, as well as DON-derived prodrugs. We discuss their mechanisms of action and their integration with chemotherapy, targeted therapies, radiotherapy, and immunotherapy, highlighting how glutamine metabolism targeting influences tumor metabolic adaptation, redox homeostasis, therapy resistance, and tumor-immune interactions. Finally, we examine current clinical developments, emerging therapeutic combinations, and the challenges that must be addressed for the incorporation of glutamine metabolism targeting into precision oncology.

Keywords:  BPTES; CB-839; DON; DRP-104; combination therapy; glutaminase; synergistic effects

DOI:  https://doi.org/10.3390/pharmaceutics18070850
Anim Biosci. 2026 Jul 27.

Integrated Metabolomic and Transcriptomic Analyses Reveal that Glutamine Promotes Chicken PGCLC Specification Potentially through α-Ketoglutarate.

Qingqing Geng, Lei Zhang, Zhe Wang, Kunyu Liang, Fufu Cheng, Jing Chen, Yifan Xi, Junqiang Hou, Xinyue Jiao, Farooq Mazhar, Sheng Cui, Yani Zhang.

   Objective: Primordial germ cell (PGC) is essential for germline transmission and genetic resource conservation in poultry. Although several genes and signaling pathways involved in PGC specification have been identified, the upstream regulatory mechanisms-particularly metabolic regulation and epigenetic modification-remain poorly understood. This study aimed to characterize the metabolic landscape underlying chicken PGC formation and identify key metabolic regulators involved in BMP4-induced primordial germ cell‑like cell (PGCLC) specification in vitro.
Methods: Untargeted metabolomics and transcriptomics were performed to compare metabolic profiles and gene expression patterns between chicken embryonic stem cell (ESC) and PGC. Differential metabolites and metabolism-related genes were identified through integrated multi-omics analysis. Functional experiments, including glutamine deprivation and metabolite supplementation, were conducted to verify the role of glutamine metabolism in PGCLC specification.
Results: A total of 194 differentially expressed metabolites (DEMs) were identified, mainly enriched in amino acid, nucleotide, energy metabolism, and antioxidant pathways. Compared with ESC, PGC contained higher levels of amino acids, peptides, and benzoic acid derivatives, whereas carbohydrates were more abundant in ESC. Transcriptomic analysis of 14,405 annotated genes revealed similar metabolic gene expression patterns in male and female samples. Integrated analysis indicated that amino acid metabolism, particularly glutamine metabolism, plays a key role in PGC formation. Glutamine deprivation significantly inhibited PGCLC specification, disrupted the balance between glycolysis and oxidative phosphorylation, and altered H3K4me2 epigenetic modification. Supplementation with the glutamine-derived tricarboxylic acid (TCA) cycle metabolite α-ketoglutarate (α-KG) markedly restored the reduced efficiency of PGCLC specification caused by glutamine depletion.
Conclusion: Glutamine promotes chicken PGCLC specification and is associated with alterations in cellular metabolism and increased H3K4me2 levels during differentiation. These findings suggest a potential association between glutamine metabolism, α-KG, and epigenetic regulation during germ cell development, providing new insights into the metabolic basis of PGC formation and a foundation for improving PGC culture and expansion in poultry.

Keywords:  amino acids; glutamine metabolism; primordial germ cell; primordial germ cell-like cell; α-ketoglutarate

DOI:  https://doi.org/10.5713/ab.260260
bioRxiv. 2026 Jul 13. pii: 2026.07.09.735845. [Epub ahead of print]

Glutamine Metabolism Supports α cell Mass and Glucagon Secretion.

Anna Marie R Schornack, Tyler J Rodgers, Matthew Shou, Walter A Siv, Linlin Yin, Katelyn Sellick, Varsha Chigurupati, Joshua Debo, Soham Saraf, Paula G Nickles, Selina Park, Shannon E Gibson, Nitin Shankar, Jordyn R Dobson, Soma Behera, Jade E Stanley, Angelina Ehara, Madushika Wimalarathne, Amber Crabtree, Austin Reuter, Alan Attie, Elma Zaganjor, Katie C Coate, Yan Li, Jeffrey C Rathmell, Mark P Keller, David A Jacobson, Wenbiao Chen, E Danielle Dean.

The liver-α cell axis is a finely tuned biological rheostat that regulates whole body amino acid availability. Pancreatic α cells secrete glucagon that regulates amino acid catabolism through gluconeogenesis and ureagenesis, yet the mechanisms linking amino acid levels to α cell growth and function are not fully understood. Here, we identify glutaminase, the enzyme that catalyzes glutamine catabolism, as a critical α cell regulator. Glutaminase is highly enriched in α cells across species. α cell expression of glutaminase is required for nutrient-dependent mTORC1 activation, suppression of AMPK signaling, and sustained expression of the glutamine transporter SLC38A5. This establishes a feed-forward loop linking glutamine metabolism to amino acid sensing and growth. Reduced glutaminase activity impairs dynamic glucagon secretion in response to low glucose and amino acids. Together, these findings highlight the importance of glutamine metabolism in α cell growth and hormone secretion and suggest it may play a role in α cell adaptation to hyperaminoacidemia.

DOI: https://doi.org/10.64898/2026.07.09.735845
J Bioenerg Biomembr. 2026 Jul 30. pii: 42. [Epub ahead of print]58(1):

Application of glutamine metabolism-related gene signatures in the non-invasive diagnosis of coronary artery disease: integrating bulk and single-cell transcriptomics.

Zhiyong Zhao, Yu Li, Junpeng Li, Yongqian Gao, Zhijun Yan, Hui Li, Qiuli Liu.

  Coronary artery disease (CAD) is a common cardiovascular disorder strongly associated with glutamine metabolism. This study seeks to identify novel glutamine metabolism-related gene markers in CAD. Based on GEO datasets and glutamine metabolism-related genes, hub genes were pinpointed through WGCNA combined with LASSO, SVM-RFE, and random forest algorithms. Immune cell infiltration was estimated with the CIBERSORT algorithm. To confirm the expression and roles of hub genes, ox-LDL-stimulated HUVECs were analyzed in culture. MYBPC3 and TRIM47 emerged as candidate diagnostic signatures for CAD. Associations between MYBPC3/TRIM47 and immune cell infiltration were revealed. Upregulation of MYBPC3 and TRIM47 in CAD was confirmed in both GSE113079 and ox-LDL-treated HUVECs. Knockdown of TRIM47 or MYBPC3 promoted ox-LDL-induced proliferation of HUVECs, alleviated cellular apoptosis, and suppressed the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) as well as M1 macrophage polarization. MYBPC3 and TRIM47 may serve as candidate diagnostic signatures for CAD.

Keywords:  Bulk RNA transcriptome; Coronary artery disease; Glutamine metabolism; Non-invasive diagnosis; Single-cell transcriptome

DOI:  https://doi.org/10.1007/s10863-026-10125-x
Biochim Biophys Acta Gene Regul Mech. 2026 Jul 27. pii: S1874-9399(26)00034-9. [Epub ahead of print] 195168

NMN alleviates oxidative stress damage in alopecia areata by activating SIRT7 and promoting glutamine metabolism.

Tianyu Cao, Lan Jiang, Lin Liu, Na Wang, Da Zhai, Ling Liu.

  Alopecia areata (AA) is an autoimmune disorder characterized by oxidative stress-induced dysfunction of hair follicle stem cells (HFSCs). Nicotinamide mononucleotide (NMN), a precursor of NAD+, exhibits antioxidant properties, but its role and mechanism in AA remain unclear. This study aimed to investigate the therapeutic potential of NMN and its underlying mechanism. Scalp tissues from AA patients and healthy controls were collected, and HFSCs were isolated. An in vitro oxidative stress model was established using H2O2. Cell viability, apoptosis, migration, oxidative stress and glutamine metabolism were assessed. Molecular mechanisms were investigated via gene knockdown (sh-SIRT7, sh-GLS1) and rescue experiments with an acetylation-resistant GLS1 mutant (GLS1-MUT). An in vivo mouse model of H2O2-induced hair follicle damage was utilized for validation. The results showed that NMN (2 mM) significantly enhanced the viability, migration, and differentiation capacity of both AA-derived and H2O2-induced HFSCs, while cell apoptosis and oxidative stress were repressed. NMN also promoted glutamine metabolism with increased GSH, glutamate, glutamine and NAD+ levels, as well as elevated GPx and GLS1 activities. Mechanistically, SIRT7 expression was downregulated in AA. NMN restored SIRT7 expression and activity, leading to the deacetylation and activation of GLS1. Knockdown of SIRT7 or GLS1 abolished NMN's protective effects, which were rescued by GLS1-MUT, establishing a linear pathway. In vivo, NMN treatment alleviated H2O2-induced hair follicle damage, promoted regeneration, and preserved SIRT7 expression in the stem cell niche. In conclusion, NMN alleviates oxidative stress and improves HFSC function in AA by activating the SIRT7-GLS1 axis and enhancing glutamine metabolism, revealing a novel therapeutic target for AA.

Keywords:  Alopecia areata; Glutamine metabolism; NMN; SIRT7

DOI:  https://doi.org/10.1016/j.bbagrm.2026.195168
Magn Reson Lett. 2027 Feb;7(1): 200293

Real-time NMR analysis of glutamine metabolism for screening anti-cancer agents in living cells.

Yating Lei, Tao Huang, Xin Chai, Xinyu Fan, Sipei He, Caixiang Liu, Maili Liu, Xu Zhang.

  Metabolic reprogramming is a substantial obstacle for anticancer drug screening, as targeted therapeutics often lose efficiency due to the dynamic adaption of cancer cells. Glutamine metabolism in cancer profoundly impacts tumor initiation, progression and metastasis. The existing agents are compromised by resistance and off-target toxicity. In this study, a real-time NMR tracking method for intracellular glutamine metabolic flux was established. This method enables comprehensive profiling of nitrogen metabolism and serves as a valuable tool for characterizing specific cancer metabolic phenotypes and screening drugs against targeted cancer cells. Applying this approach to traditional Chinese medicine (TCM) discovery, we identified Astragalus membranaceus as a potent regulator of glutamine metabolism. Through virtual screening via molecular docking, 12 potential compounds from Astragalus membranaceus were initially flagged as candidate binders toward the allosteric pocket of glutaminase 1 (GLS1). Crucially, subsequent in vitro recombinant human GLS1 enzyme activity assays successfully ruled out computational false positives and demonstrated that Compound 2 (quercetin) acts as the exclusive, direct enzymatic inhibitor among the tested monomers, capable of effectively suppressing GLS1 activity. Overall, this work provides a robust platform for real-time metabolic profiling of glutamine metabolism and drug screening at the living cell level, and offers new insights into the mechanisms of TCMs in anticancer therapy.

Keywords:  Astragalus membranaceus; Drug screening; Glutamine metabolism; Living cells; Real-time NMR

DOI:  https://doi.org/10.1016/j.mrl.2026.200293
Front Oncol. 2026 ;16 1849888

Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming.

Egiroh Omene.

  Glioblastoma (GBM) remains the most lethal primary brain tumour, with median overall survival of 14 to 16 months despite maximal safe surgical resection, concurrent chemoradiotherapy, and adjuvant temozolomide. Treatment failure is driven in large part by a profoundly immunosuppressive tumour microenvironment (TME) in which metabolic competition between GBM cells, bone marrow-derived immunosuppressive myeloid cells, and cytotoxic T lymphocytes determines cellular dominance. This review frames the GBM TME through the lens of metabolic cell competition: a process by which differential metabolic fitness, mediated principally through glucose and glutamine consumption, establishes a suppressive hierarchy that forecloses effective anti-tumour immunity. Aerobic glycolysis in GBM cells produces lactate, which polarises tumour-associated macrophages toward immunosuppressive phenotypes via GPR81/HIF-1alpha signalling and directly impairs T cell effector function through extracellular acidification and competition for monocarboxylate transporter capacity. GBM cells and immunosuppressive myeloid cells cannot sustain their proliferative and immunosuppressive programmes without glucose and glutamine; cytotoxic memory T cells, whose effector functions are energetically but not biosynthetically demanding, retain the capacity to function through fatty acid oxidation when these substrates are restricted. Disrupting glucose and glutamine metabolism through glutamine antagonism (DON and prodrugs JHU083/JHU395), dichloroacetate (DCA)-mediated PDK inhibition, intravenous pharmacological ascorbate-mediated GAPDH inactivation and HIF-1alpha destabilisation, systemic glucose restriction (SGLT2 inhibitors), sodium phenylbutyrate-mediated glutamine depletion, and monocarboxylate transporter inhibition can invert this competitive hierarchy, reprogramming the immunosuppressive myeloid compartment while preserving T cell fitness; mebendazole is additionally reviewed as a multi-target anti-parasitic repurposing candidate with demonstrated GBM preclinical survival benefit. Pharmacological ketosis elevates beta-hydroxybutyrate, an endogenous HDAC inhibitor that further augments T cell effector function through NLRP3 inflammasome suppression. The mechanistic and clinical evidence for each intervention is reviewed, metabolic engineering strategies for increasing T cell competitive fitness are described, and principal research gaps are identified. GBM cells and immunosuppressive myeloid cells are proposed to constitute a substrate-dependent competitive coalition whose simultaneous disruption is the central therapeutic proposition reviewed. Evidence is synthesised from in vitro metabolic competition experiments, immune-competent murine GBM models, mechanistic pharmacology studies, and early-phase clinical pharmacodynamic data in human GBM.

Keywords:  fatty acid oxidation; glioblastoma; glutamine metabolism; glycolysis; metabolic cell competition; pharmacological immunometabolism; tumour microenvironment; tumour-associated macrophages

DOI:  https://doi.org/10.3389/fonc.2026.1849888
Cell Metab. 2026 Jul 30. pii: S1550-4131(26)00295-0. [Epub ahead of print]

HEBP2-governed glutamine competition between tumor and macrophages dictates immunotherapy efficacy in triple-negative breast cancer.

Yi Xiao, Ying Xu, Han Wang, Fan Yang, Xiao-Hong Ding, Tong Fu, Li Chen, Xi Jin, Ya-Xin Zhao, Ying Wang, Fenfang Chen, Zhi-Ming Shao, Yi-Zhou Jiang.

DOI: https://doi.org/10.1016/j.cmet.2026.07.022
Toxics. 2026 Jul 10. pii: 602. [Epub ahead of print]14(7):

Nrf2 Activation Alleviates Silica-Induced Toxicity in Alveolar Macrophages via Glutamine Metabolic Reprogramming.

Xinyi Zhu, Jixia Hu, Fangguo Lu, Ziyi Liu, Zhibin Wang, Chang Liu, Quan Zhu, Jun Lu.

  As a major occupational hazard, crystalline silica (SiO2) poses a severe risk of pulmonary toxicity. While the irreversible fibrosis of late-stage silicosis has been extensively studied, the cellular and molecular mechanisms by which SiO2 reprograms macrophage metabolism to drive early pathogenesis remain poorly understood. To elucidate this early immune-inflammatory response, we combined targeted metabolomics, pharmacological treatments, and nutrient deprivation in murine alveolar macrophages. Our results demonstrate that SiO2 exposure severely impairs the master antioxidant regulator, nuclear factor erythroid 2-related factor 2 (Nrf2), triggering excessive reactive oxygen species (ROS) accumulation and upregulated glutamine catabolism to drive pro-inflammatory M1 macrophage polarization. We demonstrated that Nrf2 activation with tert-butylhydroquinone (TBHQ) redirected glutamine metabolic flux from pro-inflammatory catabolism to antioxidant anabolism, significantly attenuating SiO2-induced M1 polarization. Conversely, Nrf2 inhibition via ML385 exacerbated the inflammatory response. Furthermore, introducing a glutamine deprivation (-Gln) model revealed that restricting glutamine availability significantly attenuated the ability of Nrf2 to reverse M1 polarization, suggesting that its immune-protective effects largely depend on an intact glutamine metabolic pathway. Ultimately, our findings underscore the severe risks of silica exposure and identify the Nrf2-glutamine metabolic axis as a promising target, providing novel mechanistic insights and a robust basis for "antioxidant-metabolic" dual-target interventions in early-stage silicosis.

Keywords:  M1 phenotype; Nrf2; alveolar macrophages; crystalline silica; metabolic reprogramming

DOI:  https://doi.org/10.3390/toxics14070602
Curr Issues Mol Biol. 2026 Jul 16. pii: 724. [Epub ahead of print]48(7):

Metabolic Reprogramming in Oral Cancer: A Narrative Review of Therapeutic Perspectives with Emphasis on Dichloroacetate.

Sara Senlle, Cécile Nicole, Patrícia M A Silva, Odília Queirós, Andrea Cunha.

  Oral squamous cell carcinoma (OSCC) represents a significant global health challenge characterized by high morbidity and mortality, frequently driven by therapeutic resistance and tumor aggressiveness. Metabolic reprogramming has emerged as a hallmark of OSCC, enabling tumor cells to sustain proliferation, survive under adverse microenvironmental conditions, and evade therapeutic stress. Recent advances in cancer metabolism have identified metabolic plasticity as a central determinant of OSCC progression and treatment failure, highlighting the need to integrate evidence on metabolic vulnerabilities and therapeutic opportunities. This narrative review aims to provide an updated overview of metabolic reprogramming in OSCC, with particular emphasis on the interplay between glycolysis, mitochondrial metabolism, glutamine metabolism, and fatty acid oxidation, and to discuss how these interconnected pathways may be therapeutically exploited. Although OSCC cells exhibit enhanced aerobic glycolysis, mitochondria remain functionally active and play critical roles in energy production, redox homeostasis, and metabolic adaptation. The therapeutic potential of targeting tumor metabolism is discussed, highlighting dichloroacetate (DCA) as a promising metabolic modulator capable of inhibiting pyruvate dehydrogenase kinase (PDK), restoring mitochondrial glucose oxidation, and partially reversing the glycolytic phenotype. The review also examines the current translational limitations of DCA, including toxicity, pharmacokinetic constraints, and compensatory metabolic adaptations that restrict its efficacy as a standalone therapy. Furthermore, potential synergistic strategies are explored, particularly the combination of DCA with paclitaxel, which enhances therapeutic efficacy through concurrent disruption of cytoskeletal integrity and metabolic homeostasis, thereby increasing cellular susceptibility to apoptosis and overcoming chemoresistance.

Keywords:  Warburg effect; dichloroacetate; drug resistance; oral cancer; tumor metabolism

DOI:  https://doi.org/10.3390/cimb48070724
MedComm (2020). 2026 Aug;7(8): e70886

Amino Acid and Lipid Metabolism in Cancer: Mechanisms and Therapeutic Opportunities.

Zixu Wang, Xin Fu, Jingchao Bai, Yanguo Liu, Kai Huang.

  Metabolic reprogramming is a defining feature of cancer and a major contributor to immune escape. Beyond the well-defined glycolysis, dysregulated amino acid and lipid metabolism also regulate tumor growth, stress adaptation, and therapeutic resistance. Amino acids such as glutamine, arginine, tryptophan, methionine, serine, and cysteine shape biosynthesis, redox balance, one-carbon metabolism, epigenetic control, and nutrient competition in the tumor microenvironment. Lipid uptake, de novo lipogenesis, fatty acid oxidation, cholesterol remodeling, COX-PGE2 signaling, sphingolipid metabolism, and ferroptosis further influence antigen presentation, immune cell fitness, and checkpoint regulation. However, most studies still consider these metabolic axes separately, leaving the coordinated amino acid-lipid crosstalk across tumor and immune compartments insufficiently defined. This review synthesizes recent advances in amino acid metabolism, including the glutamine axis, arginine-polyamine biology, the tryptophan-kynurenine-AHR pathway, and methionine-dependent methylation programs. It then discusses lipid metabolic programs that regulate dendritic cell cross-presentation, suppressive myeloid polarization, CD8+ T cell exhaustion, PD-L1 palmitoylation, MHC-I stability, and lipid-peroxidation-linked ferroptosis. We further integrate nutrient competition, immunometabolic checkpoints, and dual metabolic targeting strategies with immune checkpoint blockade. This review provides a unified framework for identifying metabolic vulnerabilities, designing rational combination therapies and refining precision cancer immunotherapy.

Keywords:  amino acid metabolism; cancer immunotherapy; immune evasion; lipid metabolism; metabolic reprogramming

DOI:  https://doi.org/10.1002/mco2.70886
Int J Mol Sci. 2026 Jul 11. pii: 6206. [Epub ahead of print]27(14):

Microenvironment-Driven Reprogramming in Colorectal Cancer Liver Metastasis: Metabolic, Phenotypic, and Immune Adaptation.

Xiaoli Mu, Wenjun Meng, Lingnan Zheng.

  Liver metastasis is a major cause of mortality in patients with metastatic colorectal cancer and reflects the selective pressures imposed by the hepatic niche. This review summarizes how the liver microenvironment may reshape disseminated colorectal cancer cells through three interconnected programs: metabolic reprogramming, phenotypic plasticity, and immune evasion. Metabolically, metastatic cells adapt to the glucose-poor and lipid-rich hepatic milieu by switching between glycolysis and oxidative phosphorylation, activating gluconeogenesis, increasing glutamine dependence, and remodeling lipid utilization. Phenotypically, stromal cues such as TGF-β and HGF may promote epithelial-mesenchymal plasticity, thereby supporting invasion, survival, and metastatic outgrowth. Immunologically, the hepatic niche facilitates immune escape through PD-L1 upregulation and the recruitment or polarization of suppressive myeloid and regulatory T-cell populations. We further discuss therapeutic opportunities arising from these vulnerabilities, including inhibition of metabolic dependencies, blockade of TGF-β/FAK-driven plasticity, and combination immunotherapy targeting the PD-1/PD-L1 axis together with the liver immune microenvironment. Finally, we highlight the need for biomarker-guided patient stratification, more faithful preclinical models, and rational combination strategies to overcome adaptive resistance and improve outcomes in colorectal liver metastasis.

Keywords:  colorectal cancer; epithelial–mesenchymal plasticity; immune evasion; liver metastasis; metabolic reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27146206
Mol Nutr Food Res. 2026 Aug;70(15): e70536

The Preventive Effect of Introducing Glutamine on Chemotherapy-Induced Diarrhea in Colorectal Cancer and Its Influence on Inflammatory Factors Such as CRP and IL-6.

Jianwei Zhu, Yang Liu.

  To assess the protective effects of live combined bifidobacterium, lactobacillus, enterococcus, and glutamine on diarrhea associated with chemotherapy and inflammatory markers in colorectal cancer patients (CCP). A retrospective analysis was conducted on the clinical data of patients with colorectal cancer who received chemotherapy at the People's Hospital of Pailin County, Chongqing from December 2022 to December 2024. There were 59 cases in the control group and 59 cases in the study group. The control group received treatment with triple live bifidobacterium, while the study group received combined treatment with glutamine in addition to the treatment of the control group. We compared levels of inflammatory markers, intestinal barrier functions, immune responses, and diarrhea incidence during chemotherapy. No significant pre-chemotherapy differences were noted in inflammatory or intestinal barrier markers (P > 0.05). Throughout the course of treatment, we observed a reduction in inflammatory markers in both groups (P < 0.05), with the experimental group showing more significant declines. Intestinal barrier functions degraded over time in both groups, with more significant reductions in the study group (P < 0.05). The therapy combining significantly mitigates inflammation, bolsters intestinal and immune functions, and alleviates diarrhea in CCP. Clinical Registration: The authors have nothing to report.

Keywords:  bifidobacterium lactobacillus and enterococcus; chemotherapy; colorectal cancer; diarrhea; glutamine; inflammatory factors

DOI:  https://doi.org/10.1002/mnfr.70536
Immunohorizons. 2026 Jul 10. pii: vlag025. [Epub ahead of print]10(7):

Dysregulated myelopoiesis and enhanced glutaminase-dependent neutrophil survival in preclinical obesity.

Madison Babcock, Aric Lechner, Julia Drolet, Lynn Agostini, Ruth Weinstock, Norifumi Urao.

  Obesity is increasingly recognized as a state of chronic low-grade inflammation associated with altered immune cell function, yet the mechanisms driving these changes remain incompletely understood. This study investigated myeloid cell subpopulations and neutrophil behavior in adult participants exhibiting preclinical obesity (body mass index [BMI] 32-51 kg/m2, n = 12) compared to normal-weight controls (BMI 21-24 kg/m2, n = 9), correlating findings with metabolic and inflammatory markers. Peripheral blood samples were analyzed by flow cytometry to quantify myeloid cell populations and TLR4/IL-1R surface expression. Neutrophils were cultured under normoxic (18% O2) or hypoxic (1% O2) conditions, with or without glutaminase inhibition, to assess spontaneous neutrophil death. Participants with preclinical obesity exhibited increased monocyte numbers and eosinophils, whereas total neutrophil numbers were not significantly different between groups, together with a higher percentage of HLA-DR-/low monocytes and activated immature (CD16-CD11b+CD10-) neutrophils. In participants under 60 yr of age, IL‑1R expression on monocytes was significantly increased in the obesity group. Significant metabolic differences were also noted, including higher A1c (5.9 ± 0.1% vs 5.3 ± 0.1%), hs-CRP (9.01 ± 3.33 vs 0.69 ± 0.17 mg/L), and alkaline phosphatase (102.33 ± 9.67 vs 65.75 ± 5.54 U/L) in the preclinical obesity cohort, alongside decreased mean cell hemoglobin. Ex vivo neutrophil culture revealed that hypoxia reduced spontaneous neutrophil death in both groups; however, this effect was significantly reduced by glutaminase inhibition specifically in neutrophils from participants with preclinical obesity, suggesting a heightened reliance on glutamine metabolism for survival under hypoxia. These findings demonstrate dysregulated myelopoiesis and altered neutrophil behavior in preclinical obesity, providing mechanistic insight into the early immune consequences of metabolic dysfunction.

Keywords:  apoptosis; hematopoiesis; human; monocytes/macrophages; neutrophils

DOI:  https://doi.org/10.1093/immhor/vlag025
Nutrients. 2026 Jul 21. pii: 2381. [Epub ahead of print]18(14):

Perioperative Immunonutrition in Patients Undergoing Lung Cancer Surgery: Current Evidence and Future Perspectives.

Alicja Werblińska, Piotr Jerzy Skrzypczak, Magdalena Roszak, Maciej Bryl, Cezary Piwkowski, Piotr Gabryel.

  Background/Objectives: Lung cancer remains the leading cause of cancer-related mortality worldwide, and surgical resection is the primary curative treatment for patients with early-stage non-small cell lung cancer (NSCLC). Patients undergoing lung cancer surgery are frequently affected by malnutrition, systemic inflammation, sarcopenia, and cancer-related cachexia, which may adversely affect postoperative recovery and clinical outcomes. Perioperative immunonutrition has been proposed as a strategy to support immune and metabolic responses associated with surgical stress. This narrative review summarizes current evidence regarding the role of perioperative immunonutrition in patients undergoing lung cancer surgery. Methods: This narrative review summarizes current evidence regarding perioperative immunonutrition in patients undergoing lung cancer surgery. Relevant studies evaluating perioperative immunonutrition, including formulations enriched with arginine, omega-3 fatty acids, glutamine, and nucleotides, were analyzed. Particular attention was given to clinical studies in thoracic surgical oncology, perioperative outcomes, inflammatory response, and current nutritional guideline recommendations. Results: Available evidence suggests that perioperative immunonutrition may improve nutritional and immunological status in patients undergoing lung cancer surgery. Clinical studies have reported reductions in postoperative complications, shorter chest drainage duration, improved nutritional indices, and decreased inflammatory markers in patients receiving immunonutritional support. Experimental and translational studies also indicate potential beneficial effects on immune cell function and inflammatory regulation. However, current thoracic-specific evidence remains limited because of small study populations, heterogeneity of nutritional protocols, and variability in study design. Conclusions: Perioperative immunonutrition appears to be a promising adjunct to comprehensive perioperative care in patients undergoing lung cancer surgery. Although preliminary evidence suggests potential benefits in postoperative recovery and nutritional optimization, its implementation should be individualized according to the patient's nutritional status, disease stage, and overall treatment strategy. As immunonutrition modulates metabolic and immune pathways that may also influence tumor biology, nutritional interventions should be evidence-based, carefully monitored, and integrated within multidisciplinary perioperative care to maximize clinical benefits while minimizing potential unintended effects. Further large, well-designed randomized clinical trials are needed to establish standardized protocols and clarify the role of immunonutrition in thoracic surgical oncology.

Keywords:  immunonutrition; lung cancer; perioperative care; thoracic surgery

DOI:  https://doi.org/10.3390/nu18142381