bims-glucam 2026-07-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2026–07–05
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.
Size switchable nanomodulator achieving ratio-precise dual-drug codelivery for synergistic glutamine metabolism modulation in pancreatic cancer.
Vitamin D supports activated CD4+ T-cell proliferation through enhanced glutaminolysis.
YTHDC2 suppresses oral squamous cell carcinoma progression by inhibiting glutaminolysis via VHL/HIF-1α axis.
Integrated Proteomics and Metabolomics Analysis Provides Insights into Metformin Down-regulating GLUL and SP1 to Inhibit Esophageal Squamous Cell Carcinoma Migration and Invasion.
Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.
The effects of glutamine supplementation on inflammatory and oxidative stress indices in chronic diseases: a systematic review.
Histidine to glutamine substitutants, a regulated process that impacts cell survival and suggests histidine shortage in cancer.
GPX1 Drives Cuproptosis-Ferroptosis Resistance in Cold Tumors.
Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.
Decoding amino acid metabolism in hepatocellular carcinoma: critical nodes and novel therapeutic strategy.
Metabolic Flux Analysis Reveals Cell Line-Specific Rewiring in CHO Cells Following TCA Cycle Intermediate Feeding for Bioprocess pH Control.
Metabolic inhibition of glutamate-cysteine ligase increases dendritic cell-mediated antitumor immunity in melanoma.
GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling.
Bioengineered miR-148a-3p suppresses glycolysis and amino acid homeostasis in hepatocellular carcinoma cells by regulating multiple solute carrier transporters.
Forging New Pathways in Oncology: Strategic Insights from the 17th Annual Frontiers in Cancer Science Conference.
Neural-tumor crosstalk in driving tumor metabolic reprogramming.
The multifaceted roles of mitochondria and their therapeutic transformation: a new perspective on triple-negative breast cancer treatment.
Redox Metabolism and Metabolic Vulnerabilities in Diabetes-Driven Pancreatic Cancer: Targeting System Xc-, mTORC1, and Disulfidptosis as Therapeutic Strategy.
HOTAIR at the metabolic crossroads: lncRNA control of carbohydrate and lipid metabolism.
Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Mechanisms and Therapeutic Strategies.
Phillygenin suppresses hepatocellular carcinoma progression by modulating the TNF signaling pathway and TCA cycle metabolism.
Targeting the cancer metabolism-immunity interface: update and perspectives.

Cancer Genomics Proteomics. 2026 Jul-Aug;23(4):23(4): 629-648

Glucose and Glutamine Define Independent Activation-Braking Metabolic States in Triple Negative Breast Cancer Cells.

Elizabeth A Mazzio, Renee Reams, Ramesh B Badisa, Jean Baptiste Lamango, Zonelle Hanley, Karam F A Soliman.

   BACKGROUND/AIM: Cancer metabolism is often viewed as a cooperative reliance on glucose and glutamine; however, whether these nutrients can enforce discrete, non-overlapping metabolic states remains unclear. This study aimed to isolate nutrient-specific regulatory programs.
MATERIALS AND METHODS: MDA-MB-231 human breast cancer cells were cultured under four distinct metabolic environments: glucose/glutamine nutrient-repleted (fed), dual glucose/glutamine deficiency, and isolated repletion of either glucose or glutamine. Groups were evaluated for integrated transcriptomic, metabolomic, and lipidomic profiles to identify only the non-redundant, nutrient-enforced architectures.
RESULTS: The data show a mutually restrictive mechanistic state. Glutamine functions as a metabolic architect, restoring glycolytic enzyme transcripts (without lactate production), while inducing PDK1/3 which would decouple glycolysis from the TCA cycle. These changes are concomitant with a glutamine flux toward reductive TCA-driven lipogenesis, citric acid overflow, sterol synthesis (SREBF1/2), structural membrane expansion (phospholipids/sphingolipids) and the unique production of alanine as a nitrogen pool, independent of glycolytic flux. Conversely, glucose alone acts as the executor, licensing chromatin engagement, DNA replication, and mitotic progression. Glucose alone resolved ER stress, restored hexose-phosphate-derived glycosylation (mannose-6-phosphate), enabled lactic acid production, and diverted excess carbon into a triglyceride storage pool (>40% of lipids). Notably, each nutrient suppressed core elements of the other's program, revealing a reciprocal activation-braking system. Interestingly, ATP yield from glucose or glutamine alone were comparable, but not arbitrary; instead, aligned with the functional state of the cell. Glucose alone supported glycolytic phosphorylation and proliferative execution, as marked by lactate accumulation, whereas glutamine alone supported Krebs cycle-related phosphorylation, characterized by citrate accumulation and the maintenance of cellular structure and membrane infrastructure.
CONCLUSION: Glucose and glutamine enforce a balance of two independent, reciprocally regulated metabolic states. This data provides a systems-level explanation for metabolic resilience in cancer and may lead to the identification of nutrient-specific targets for combination therapy.

Keywords:  Cancer metabolism; ER stress; PDK; Warburg effect; anaplerosis; breast cancer; glucose–glutamine reciprocity; glutaminolysis; lipid remodeling; metabolic plasticity; nutrient-enforced metabolic states; oxidative phosphorylation; pyruvate dehydrogenase kinase; substrate-level phosphorylation; transcriptional state control

DOI:  https://doi.org/10.21873/cgp.20593
Biomaterials. 2026 Jun 24. pii: S0142-9612(26)00430-8. [Epub ahead of print]335 124406

Size switchable nanomodulator achieving ratio-precise dual-drug codelivery for synergistic glutamine metabolism modulation in pancreatic cancer.

Hongrui Fan, Xuwen Li, Haolin Song, Shilin Zhang, Zonghua Tian, Yun Chen, Jingyi Zhou, Shuo Geng, Huiyi Liu, Yiying Wang, Tao Sun, Chen Jiang.

  Under the nutrient-deprived tumor microenvironment (TME) and near-universal KRAS mutations, pancreatic ductal adenocarcinoma (PDAC) exhibits voracious addiction to glutamine metabolism. This aberrant metabolism not only sustains the rapid proliferation of malignant cells, but also shapes a tumor-permissive TME characterized by stromal desmoplasia and immunosuppression, culminating in the clinical refractoriness of PDAC. Although multi-target synergistic modulation of glutamine metabolism is recognized as a requisite antitumor strategy, its implementation is still hampered by the uncontrolled in vivo multi-drug biodistribution. Therefore, glutamine metabolism modulation is in urgent need of precision codelivery of multiple drugs. Herein, we propose an upstream-downstream synergistic glutamine metabolism modulation strategy and develop a size switchable metabolic nanomodulators (J&V@T-PPLN NPs) for precision codelivery of metabolic modulators. This nanomodulator achieves in vivo ratio-precise dual-drug codelivery, synergistically blocking the uptake and utilization of glutamine by PDAC cells. Beyond cutting off nutrient supply to malignant cells, the nanomodulator also demonstrates the capacity to remodel the TME and reactivate antitumor immunity, thereby eliciting enhanced tumor suppression. Through the ratio-precise codelivery system, this study discussed the possibility of translating in vitro validated synergistic metabolism modulation into a controllable in vivo combination therapy modality, providing a generalizable strategy for metabolism modulating cancer therapy and the rational design of precision drug delivery systems.

Keywords:  Glutamine addiction; Metabolic nanomodulator; Metabolism-immune crosstalk; Pancreatic ductal adenocarcinoma; Tumor metabolism microenvironment

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124406
Front Immunol. 2026 ;17 1791098

Vitamin D supports activated CD4+ T-cell proliferation through enhanced glutaminolysis.

Agustín A Vera, Mauricio Hernandez, Ricardo A Cartes, Faryd Llerena, Solange E Cisterna, Romina A Quiroga, Sergio A Sanhueza, Camila P Muñoz-Grez, Francisco Vergara, Daniel Moena, Pablo A Alarcón, Rafael Burgos, Coralia I Rivas, Elena Uribe, Rafael J Argüello, Cristopher Almarza, Felix A Urra, Francisco Tapia-Belmonte, Luciano Ferrada, Liliana I Lamperti, Estefanía Nova-Lamperti.

   Background: Vitamin D (VitD) is an important immunometabolic regulator of T cell function. Its active form, 1,25-dihydroxyvitamin D3, signals through the VitD receptor (VDR), which is highly expressed in activated CD4+ T cells. Although VDR signaling suppresses glycolysis by reducing glucose uptake and glycolytic enzyme expression, early T cell expansion is preserved, suggesting the involvement of alternative metabolic pathways. Since glutaminolysis is essential for T cell activation and proliferation, we investigated whether VitD modulates glutamine metabolism during early CD4+ T cell activation.
Methods: Human CD4+ T cells were stimulated with αCD3/CD28 for four days in the presence or absence of VitD, and analyzed using complementary metabolic, proteomic, and functional approaches.
Results: VitD-treated cultures exhibited increased cell numbers despite reduced glucose uptake and lactate production, indicating proliferation partially independent of classical glycolytic metabolism. Proteomic analysis revealed increased expression of glutaminase, glutamate dehydrogenase, and CD38, together with enrichment of Selenium Metabolism and Selenoproteins and Nicotinate and Nicotinamide Metabolism, suggesting enhanced glutaminolysis and NAD+ remodeling. Consistently, tritiated and ¹³C-glutamine tracing demonstrated increased glutamine uptake and incorporation into glutamate, α-ketoglutarate, glucose, and inositol-related metabolites, supporting a glutaminolysis-dependent anabolic program rather than oxidative phosphorylation. Pharmacological inhibition of VDR (MeTC7, 1 nM), glutamine uptake (GPNA, 250 µM), or glutaminase activity (BPTES and compound 968, 5 µM) significantly reduced T cell expansion, highlighting glutamine metabolism as essential for the VitD-mediated cell expansion. Interestingly, prolonged cultures showed that VitD ultimately restricted proliferation at day 7; however, supplementation with glutamine and VitD restored cell expansion, suggesting that VitD promotes a metabolically restrained but adaptive proliferative state.
Discussion: Overall, our findings identify glutaminolysis as a central metabolic pathway supporting VitD-induced CD4+ T cell expansion independently of canonical glycolytic and OXPHOS-associated programs, while promoting metabolic resilience and inflammatory restraint.

Keywords:  T cell proliferation; T cell regulation; glutaminolysis; immunometabolism; vitamin D

DOI:  https://doi.org/10.3389/fimmu.2026.1791098
Int J Biol Macromol. 2026 Jun 29. pii: S0141-8130(26)03191-0. [Epub ahead of print]373 153251

YTHDC2 suppresses oral squamous cell carcinoma progression by inhibiting glutaminolysis via VHL/HIF-1α axis.

Xi Chen, Bin Yang, Zhenzhong Liu, Fang Wang, Yang Li, Ronghui Wu, Liqin Mao, Ting Zhao, Yu Gao, Yulin An.

  Oral squamous cell carcinoma (OSCC), a highly prevalent and poor-prognosis malignancy, is closely associated with tumor metabolic reprogramming, particularly the glutamine-dependent metabolic phenotype. This study systematically investigates the role of N6-methyladenosine (m6A) modification in OSCC through integrated bioinformatics analysis and functional experiments, focusing on the tumor-suppressive function of the m6A reader YTHDC2 and its regulation of glutaminolysis. Analysis based on The Cancer Genome Atlas (TCGA) datasets revealed that YTHDC2 expression was significantly inversely correlated with OSCC malignancy and patient survival. Functional validation showed that YTHDC2 depletion promoted OSCC cell proliferation and stem-like properties, whereas YTHDC2 overexpression markedly suppressed these malignant phenotypes. Mechanistic studies demonstrated that YTHDC2 stabilized VHL mRNA by recognizing m6A modification sites, enhancing VHL protein expression. This promoted VHL-mediated ubiquitin-dependent degradation of HIF-1α, leading to transcriptional repression of its downstream target GLS1. Consequently, this blocked glutaminolysis, tricarboxylic acid (TCA) cycle-driven energy production, and glutathione (GSH)-mediated antioxidant pathways. Additionally, low YTHDC2 expression in OSCC tissues was closely associated with DNA hypermethylation at CpG islands in its promoter, an epigenetic silencing mechanism that sustains the glutamine-addicted phenotype. This study first uncovers the core role of the YTHDC2/m6A/VHL/HIF-1α/GLS1 signaling axis in metabolic regulation of OSCC, providing new insights into the molecular basis of glutamine addiction. YTHDC2 not only serves as a prognostic biomarker for OSCC but also highlights its-mediated metabolic pathway as a theoretical basis for developing targeted therapies against glutaminolysis.

Keywords:  Glutaminolysis; Metabolic reprogramming; Oral squamous cell carcinoma; YTHDC2; m6A modification

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153251
Recent Pat Anticancer Drug Discov. 2026 Jun 30.

Integrated Proteomics and Metabolomics Analysis Provides Insights into Metformin Down-regulating GLUL and SP1 to Inhibit Esophageal Squamous Cell Carcinoma Migration and Invasion.

Huayu Luo, Tao Shen, Jing Zhang, Yang Cheng, Zhongyu Zhang, Yujie He, Hongzheng Ren.

   INTRODUCTION: Esophageal Cancer (EC) is a prevalent gastrointestinal malignancy. Despite significant advances in diagnostic and therapeutic approaches, the prognosis of Esophageal Squamous Cell Carcinoma (ESCC) remains poor. The development of new therapeutic agents for ESCC would greatly benefit patients and their families. Metformin has been found to be useful in other tumours, but its role and mechanism in ESCC have not been investigated.
METHODS: The effect of metformin on inhibiting invasive metastasis in ESCC cells was explored by in vitro cytology experiments. 4D-DIA proteomics and untargeted LC-MS metabolomics provided critical technical support for this study. The roles and mechanisms of differential proteins, metabolites, and key metabolic pathways in ESCC migration and invasion were further explored by identifying differentially expressed proteins and metabolites in metformin-treated ESCC cells using proteomics and metabolomics. RT-qPCR and Western blot were used to confirm metformin's inhibitory effects on key proteins in metabolic pathways associated with ESCC cell migration and invasion. Using the ESCC tissue microarray (TMA) to detect the expression levels of GLUL and SP1.
RESULTS: This study demonstrated that metformin significantly reduced ESCC cells' viability, proliferation, migration, and invasion, while enhancing apoptosis. Integrated multi-omics pathway analysis revealed the activation of several metabolic pathways following metformin treatment in ESCC cells. In vitro experiments confirmed that metformin significantly downregulated the key proteins GLUL and SP1, as identified in the differential proteomics analysis. Immunohistochemistry (IHC) showed that GLUL and SP1 expression were significantly lower in ESCC tumor tissues from patients with a history of preoperative metformin administration than in those without.
DISCUSSION: Enhanced glutamine metabolism in tumors promotes cancer progression. Downregulation of GLUL reduces glutamine production from the alanine, aspartate, and glutamate metabolic pathways, thereby inhibiting tumor progression. SP1 is an oncogenic factor in esophageal cancer and an unfavorable prognostic factor. Metformin downregulates both GLUL and SP1, affecting the alanine, aspartate, and glutamate metabolic pathways, as well as the choline metabolic pathway in cancer.
CONCLUSION: In summary, metformin may inhibit the migration and invasion of ESCC cells through downregulation of GLUL and SP1, which play important roles in the mechanism of metformin's anti-tumor effects. These findings provide new insights into the therapeutic potential of metformin in the treatment of ESCC.

Keywords:  Esophageal squamous cell carcinoma; invasion; metabolomics; metformin; migration; proteomics

DOI:  https://doi.org/10.2174/0115748928436219260622061458
Cell Rep. 2026 Jul 02. pii: S2211-1247(26)00707-2. [Epub ahead of print]45(7): 117629

Complex I drives glutamine-dependent TCA cycle to support viability of MYChigh breast cancer cells.

Johanna M Anttila, Mariel Savelius, Linda Id, Daniel Nicorici, Juhi Somani, Antti O Hiltunen, Pauliina M Munne, Aino Peura, Martina Peltonen, July Aung, Ryan Awadhpersad, Ellisiv Nyhamar, Bina Prajapati, Hanna Ala-Hongisto, Prson Gautam, Mika J Välimäki, Topi A Tervonen, Karina Šapovalovaitė, Raman Devarajan, María Victoria Ruiz Pérez, Minna Mutka, Panu Kovanen, Laura Niinikoski, Tuomo Meretoja, Johanna Mattson, Päivi Heikkilä, Krister Wennerberg, Marie Arsenian-Henriksson, Jukka Westermarck, Tero Aittokallio, Andrei Goga, Christopher B Jackson, Anni I Nieminen, Juha Klefström.

  In many cancers, stably elevated MYC levels drive sustained activation of anabolic programs and the cell cycle, creating opportunities for the synthetic-lethal targeting of MYChigh tumors. Enhanced mitochondrial respiration is a hallmark of MYC overexpressing cancer cells. Mitochondrial respiration sustains the TCA cycle by regenerating NAD+ through complex I-mediated oxidation of NADH, supporting the anabolic demand of MYC-driven cells. Metabolic carbon tracing reveals that MYC shifts the TCA cycle carbon source from glucose to glutamine. Inhibition of the glutamine-fueled TCA cycle using NAD+-depleting complex I inhibitors promotes MYC-dependent synthetic lethality in breast cancer cells. In mouse models of MYChigh tumors, combined inhibition of complex I and glutaminolysis produces persistent suppression of tumor growth. Altogether, the elevated respiration of MYChigh cells supports a glutamine carbon-enriched TCA cycle that meets anabolic demand, rendering MYChigh tumors selectively vulnerable to mitochondrial respiration and glutaminolysis inhibitors.

Keywords:  CP: cancer; CP: metabolism; MYC; TCA cycle; breast cancer; cancer; complex I; glutamine; metabolism; mitochondria; mitochondrial respiration

DOI:  https://doi.org/10.1016/j.celrep.2026.117629
Amino Acids. 2026 Jun 28.

The effects of glutamine supplementation on inflammatory and oxidative stress indices in chronic diseases: a systematic review.

Sara Movahed, Alla Bahadorkhan, Valeri Malov, Maryam Emadzadeh, Naseh Pahlavani.

  Chronic diseases are often associated with increased inflammation and oxidative stress, which contribute to disease progression. Glutamine, a conditionally essential amino acid, has been studied for its potential anti-inflammatory and antioxidant properties in various chronic conditions. The present systematic review evaluates the effects of glutamine supplementation on inflammatory markers and oxidative stress indices in patients with chronic diseases. Systematic searches were performed in web databases; Web of Science, Scopus, and PubMed/Medline until May 2025, to identify related randomized controlled trials (RCTs) according to the Cochrane Library and PICOS criteria (population: individuals > 18 years, intervention: glutamine, Comparison: placebo or control, Outcomes: inflammatory and oxidative stress markers in chronic diseases). The Cochrane collaboration tool was used to assess the risk of bias in clinical trials. Six RCTs that assessed the effect of glutamine supplementation on inflammation and oxidative stress markers were included in the study. In these studies, glutamine was administered to the participants through oral or parenteral routes. In three studies improve inflammation via significant reductions in CRP were observed. However, in three studies that examined TNF-α as an inflammatory marker, only one study found its levels to be significantly reduced. Also, of the two studies that examined oxidative stress levels, only one study significantly decreased the MDA and increased SOD levels, and in the other study, glutamine supplementation had no significant effect on glutathione levels. Our findings showed that glutamine supplementation might have a positive effect on inflammation and oxidative stress indices such as TNF-α, CRP, MDA, and SOD in some chronic diseases, however, these effects have not been shown in all studies, so more carefully designed clinical trial studies with different doses of glutamine on inflammation and oxidative stress in chronic diseases are needed. PROSPERO Code: This study was registered in the PROSPERO international prospective register of systematic reviews registration number: CRD420251049112.

Keywords:  Chronic disease; Glutamine; Inflammation; Oxidative stress

DOI:  https://doi.org/10.1007/s00726-026-03543-z
Cell Death Discov. 2026 Jun 27.

Histidine to glutamine substitutants, a regulated process that impacts cell survival and suggests histidine shortage in cancer.

Domenica Lovecchio, Pierre-René Körner, Lorenzo Valcanover, Onno B Bleijerveld, Bart R J Blokhuis, Abhijeet Pataskar, Jasmine Montenegro Navarro, Demi Wernaart, Liesbeth Hoekman, Daniil Anastasopoulos, Kim Vrijland, Xiaodong Feng, Julien Champagne, Karin E de Visser, Olaf van Tellingen, Frank A Redegeld, Reuven Agami.

Cancer-associated genetic, epigenetic, and microenvironmental factors impose shortages of tryptophan and arginine, which induce specific codon reassignments (substitutants) in their proteomes. Whether cancers are deprived of other amino acids is unknown. Histidine is an essential amino acid reported to be low in certain tumor types. Therefore, we investigated the potential for a histidine shortage in cancer. Using cultured cancer cells, we pinpointed histidine to glutamine (H>Q) substitutants as the most pronounced proteomic event following histidine deprivation. We then scanned cancer proteomes for H>Q proteins and observed a marked enrichment in pancreatic, uterine, and kidney cancers. Mechanistically, we propose that H>Q is a result of tRNA misalignment, and used tRNA glutamine (tRNA(Gln)) modifications at the wobble position to demonstrate it. We further show that URM1-mediated U34 thiolation boosts H>Q production and influences the survival of cancer cells following histidine deprivation, suggesting a potential role for H>Q. Additional characterization of H>Q substitutants revealed preferred sequences and the maintenance of H>Q host protein expression despite the absence of histidine, indicating cellular regulation and functional consequences. Thus, histidine shortage induces H>Q substitutants, a regulated mistranslation event that pinpoints histidine limitation in cancer and impacts cell survival.

DOI: https://doi.org/10.1038/s41420-026-03225-5
Free Radic Biol Med. 2026 Jul 02. pii: S0891-5849(26)00914-7. [Epub ahead of print]

GPX1 Drives Cuproptosis-Ferroptosis Resistance in Cold Tumors.

Shuang Yang, Chengye Zhang, Zhusong Mei, Qiao Ye, Guangjin Guo, Guizhen Zhu, Xiangyi Zheng, Yueying Cui, Weijie Gu, Yan Zhou, Guoquan Liu, Guangyun Wang, Zhaoting Yang.

  Cold tumors, defined by an immunosuppressive microenvironment and metabolic stress, including glutamine deficiency, frequently exhibit resistance to therapeutic interventions. This study examined the role of glutathione peroxidase 1 (GPX1) in mediating resistance to cuproptosis and ferroptosis during glutamine deprivation. Through integrated multi-omics analyses, CRISPR-mediated gene editing, and functional assays in cold tumor cell lines, we identified GPX1 as a key regulator of redox homeostasis and a protector against cuproptosis. Upstream, glutamine deprivation induced the SLC7A11 upregulation, which enhanced GPX1-mediated resistance through the maintenance of pyrimidine metabolism. Downstream, GPX1 knockout mediated cross-sensitization to ferroptosis by altering the Fenton reaction, thereby exacerbating cell death. In vivo experiments confirmed that GPX1 knockout restored sensitivity to cuproptosis inducers and improved the efficacy of PD-L1 blockade. Collectively, these findings position GPX1 as a central metabolic checkpoint in cold tumors and highlight the SLC7A11-UMPs-GPX1 axis as a promising therapeutic target for overcoming treatment resistance and enhancing immunotherapy response.

Keywords:  Cold tumors; Cuproptosis; GPX1; Glutamine deficiency; Pyrimidine metabolism

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.059
PLoS One. 2026 ;21(7): e0352639

Metabolic profiling of human melanoma cell lines with high and low metastatic capacity by 1H-NMR spectroscopy.

Nima Rezvani Kakhki, Zita Hegedűs, József Tóvári, Arash Mirzahosseini, Béla Noszál, Márta Kraszni.

BACKGROUND: Melanoma is one of the most aggressive forms of skin cancer due to its high metastatic potential and mortality rate. Although understanding of metabolic reprogramming in melanoma has advanced, the connection between metabolic alterations and metastatic capacity remains incomplete.
AIM: This study aimed to characterize the metabolic profiles of human melanoma cell lines with high (HT168-M1) and low (WM983B) metastatic potential, and to compare them with each other and also with the metabolic profile of normal human fibroblasts (MRC-5), in order to identify key metabolites and metabolic pathways associated with metastatic behavior.
METHODS: Non-targeted metabolomic profiling using ¹H-NMR spectroscopy was applied to hydrophilic extracts of the three cell lines. Multivariate statistical analyses (PCA and PLS-DA) were used to identify discriminating metabolites, and pathway analysis was performed to determine altered metabolic networks.
RESULTS: Several metabolic pathways were significantly altered in melanoma cells compared to fibroblasts, including starch and sucrose metabolism, alanine, aspartate and glutamate metabolism, and glutathione metabolism. Metabolites showing more than two-fold differences included elevated UDP-glucose, ATP, glycerophosphocholine, GTP, creatine and glutathione in the melanoma cells, and reduced glucose, glutamine and 1-methylnicotinamide in fibroblasts. Comparison of the metabolites of melanoma cell lines with differing metastatic potential revealed changes in taurine and hypotaurine, β-alanine-, glutathione-, and amino acid metabolism. Metabolites showing the largest concentration changes were UDP-glucose, glutathione, NAD+, alanine and β-alanine.
CONCLUSION: Metabolomic profiling revealed distinct metabolic reprogramming between melanoma and normal fibroblasts, characterized by enhanced glycolysis and glutathione-dependent antioxidant defense. Highly metastatic melanoma cells demonstrated stronger redox adaptation and altered amino acid utilization, with elevated glutathione and glutamate and reduced NAD⁺ and pyruvate, indicating a metabolic shift toward oxidative stress resistance.

DOI: https://doi.org/10.1371/journal.pone.0352639
Front Oncol. 2026 ;16 1806160

Decoding amino acid metabolism in hepatocellular carcinoma: critical nodes and novel therapeutic strategy.

Jiayi Zhang, Yiling Zhu, Guiyan Liu, Mengting Liao, Jianmin Wu, Chao Chen, Mengmeng Guo, Yuanye Jiang, JuanJuan Zhao, Lin Xu.

  Amino acid metabolic reprogramming is one of the crucial features of metabolic remodeling in HCC. Accumulating evidence indicates that specific amino acid metabolisms play essential roles in promoting HCC cell proliferation and the development of drug resistance. Notably, recent studies have demonstrated that regulating the intake of particular amino acids can significantly enhance the efficacy of clinical interventions for HCC, suggesting that amino acid metabolism is emerging as a promising target for therapeutic strategies. However, some key scientific questions remain unresolved, including the intrinsic relationships between the metabolism of different amino acids and their precise roles in HCC progression. In this article, we systematically review the molecular and cellular mechanisms underlying amino acid metabolic reprogramming, focusing on glutamine, arginine, and tryptophan, and explore their potential interconnections in HCC. Additionally, we update recent advances in amino acid metabolism and clinical management of HCC. Importantly, we discuss key challenges that must be addressed in future research, aiming to provide a theoretical foundation for developing novel clinical interventions targeting amino acid metabolic reprogramming in HCC.

Keywords:  amino acid metabolism; arginine; glutamine; hepatocellular carcinoma; intervention; tryptophan

DOI:  https://doi.org/10.3389/fonc.2026.1806160
Biotechnol Bioeng. 2026 Jun 28.

Metabolic Flux Analysis Reveals Cell Line-Specific Rewiring in CHO Cells Following TCA Cycle Intermediate Feeding for Bioprocess pH Control.

Sarah A Sacco, Kevin J Ruiz-Márquez, Rachel Moen, Irina Trenary, Xiaolin Zhang, Xiaowen Wang, Malik Padellan, Henry Lin, Jamey D Young.

Chinese hamster ovary (CHO) cells are the leading host for recombinant therapeutic protein production in the biopharma industry. In this study, we investigated how feeding acidic forms of tricarboxylic acid (TCA) cycle intermediates-malic acid, succinic acid, and α-ketoglutaric acid-affects cell culture performance and metabolism in two industrial IgG-producing CHO cell lines. These intermediates were used as pH control agents to replace conventional CO2 sparging, enabling simultaneous modulation of the bioreactor environment and cell metabolism. Carbon-13 metabolic flux analysis (13C-MFA) revealed substantial rewiring of central carbon and nitrogen metabolism under all fed conditions, with distinct responses between cell lines. Intermediate-fed cultures exhibited enhanced TCA cycle fluxes, reduced glucose dependency, decreased lactate accumulation, and altered routing of pyruvate. Notably, α-ketoglutaric (α-KG) acid feeding triggered divergent nitrogen assimilation phenotypes: one cell line enhanced glutamine biosynthesis and ammonium clearance, while the other accumulated glutamate with minimal glutamine production. These metabolic adaptations were accompanied by shifts in redox balance and delayed but measurable increases in cell-specific IgG productivity. Our findings highlight the compound- and cell line-specific nature of metabolic responses to TCA cycle intermediate feeding and support its use for pH control and bioprocess optimization.

DOI: https://doi.org/10.1002/bit.70287
J Immunother Cancer. 2026 Jun 30. pii: e014808. [Epub ahead of print]14(6):

Metabolic inhibition of glutamate-cysteine ligase increases dendritic cell-mediated antitumor immunity in melanoma.

Sophie Marie Dieckmann, Christoph H Tripp, Helen Strandt, Florian Hornsteiner, Annelie Kerstin Schäfer, Anastasia Prokopi, Janine Vierthaler, Antonia Resag, Daniela Ortner-Tobider, Vera Reinstadler, Irene Rigato, Berit Junger, Alexeja Kleiter, Georgios Fotakis, Mirjana Efremova, Zlatko Trajanoski, Louis Boon, Suzie Chen, Anja Katrin Bosserhoff, Herbert Oberacher, Francesca Finotello, Patrizia Stoitzner.

   BACKGROUND: Metabolic competition and nutrient restriction in the tumor microenvironment (TME) shape the immune infiltrate in tumors and subsequently tumor immunity. In this study we used the transgenic melanoma mouse model tg(Grm1)EPv, which spontaneously develops melanoma due to the ectopic expression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes to investigate if aberrant glutamate metabolism drives tumor formation and affects immune cell function.
METHODS: We performed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomic analyses and RNA sequencing on tumor-free and tumor-bearing tg(Grm1)EPv tissues to characterize metabolic alterations associated with tumor progression. Flow cytometry was used to examine changes in immune cell subsets within the TME. To assess the functional relevance of glutamate metabolism, we inhibited glutathione metabolism using L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutamate-cysteine ligase that depletes cellular glutathione levels.
RESULTS: LC-MS/MS-based metabolomic analyses and RNA sequencing revealed changes in glutamate and glutamine metabolism, a glycolytic shift (Warburg effect), and reduced ATP levels in advanced tumors compared with tumor-free tissue, suggesting respiratory chain dysfunction. These metabolic changes in the TME are advantageous for the tumor cells and unfavorable for immune cells, such as dendritic cells (DC). Indeed, flow cytometry analysis of myeloid subsets during tumor progression showed a decline in tumor-infiltrating conventional type 2 DC and macrophages, alongside an increase in neutrophil and monocyte populations in advanced lesions. Interference with glutamate metabolism using BSO induced immunogenic cell death, namely ferroptosis, in an tg(Grm1)EPv-derived cell line in vitro. Therefore, we evaluated the combination of this inhibitor with immunotherapy as a promising new approach for the treatment of tumors in the tg(Grm1)EPv mouse model. We observed that tumor growth could be delayed in vivo when BSO was combined with a therapy regimen boosting DC numbers and activation. This inhibition of tumor growth was supported by the infiltration of activated T cells.
CONCLUSION: Overall, our findings provide novel insights into the importance of combining metabolic intervention with immunotherapy for the treatment of patients with melanoma, particularly those bearing glutamate pathway-active or immunologically cold tumors. This knowledge can drive the design of novel therapeutic strategies for patients with cancer.

Keywords:  Dendritic Cells; Immunotherapy; Melanoma; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2026-014808
EMBO Rep. 2026 Jul 03.

GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling.

Imane Hadj-Aissa, Maéline Muller, Jorge Soliz, Chantelle F Sephton, Paul A Dutchak.

GATOR1 is an evolutionarily-conserved negative regulator of mTORC1-dependent signal transduction with pathogenic mutations linked to epilepsy, infantile spasms, and autism spectrum disorders. While a biochemical role of GATOR1 in amino acid-signaling is established, its cell-type specific contributions within the brain remain poorly defined. Here, we show that loss of GATOR1 function in astrocytic cells disrupts mitochondrial metabolism, with a selective dysfunction of the electron transport chain Complex II leading to elevated reactive oxygen species (ROS) and redox imbalance. These changes are accompanied by compensatory increases in antioxidant regulatory systems including superoxide dismutase, but remain insufficient to ameliorate the increased ROS. GATOR1-deficient astrocytes show metabolic rewiring marked by enhanced expression of glutamate uptake and glutamine synthesis pathways that contribute to the glutamate-glutamine cycle governing neuronal glutamine availability and synaptic homeostasis. In vivo, GATOR1 deficiency results in progressive astrocytic reactivity, seizures, and a reduced lifespan. These findings demonstrate that GATOR1 function is critical to coordinate astrocytic mitochondrial activity and neurotransmitter cycling pathways, establishing a novel link between intracellular amino acid-signaling in astrocytes and excitatory neural network homeostasis.

DOI: https://doi.org/10.1038/s44319-026-00846-w
Liver Res. 2026 Jun;10(2): 166-176

Bioengineered miR-148a-3p suppresses glycolysis and amino acid homeostasis in hepatocellular carcinoma cells by regulating multiple solute carrier transporters.

Su Guan, Xin Li, Yimei Wang, Mei-Juan Tu, Ai-Ming Yu.

   Background and aims: Hepatocellular carcinoma (HCC) cells are metabolically reprogrammed for excessive uptake and metabolism of many nutrients. The tumor suppressive microRNA-148a-3p (miR-148a-3p) is downregulated in HCC, whereas its function in regulating HCC cell metabolism remains obscure. Herein we aimed to delineate the role of miR-148a-3p in HCC cell metabolism by using novel bioengineered miR-148a-3p (BioRNALeu/miR-148a-3p) agent produced in vivo.
Methods: BioRNALeu/miR-148a-3p was designed by using human leucyl transfer RNA fused hsa-pre-miR-34a carrier, overexpressed in Escherichia coli (E. coli), and purified to high homogeneity. After transfection into HCC cells, the released miR-148a-3p levels were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell proliferation was determined by CellTiter-Glo assays. Targets were validated by dual-luciferase reporter assays, immunoblotting, and immunofluorescence confocal imaging. Glycolysis capacity was evaluated by Seahorse XF assays, and glucose, lactate, and amino acid levels were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods.
Results: BioRNALeu/miR-148a-3p was efficiently processed into target miR-148a-3p in HCC cells to effectively inhibit cell proliferation in a dose- and time-dependent manner. Mechanistically, miR-148a-3p suppressed the protein levels of glucose transporter GLUT1/SLC2A1 and L-type amino acid transporter LAT1/SLC7A5 via acting on their 3'-untranslated regions, as well as amino acid transporter ASCT2/SLC1A5. These, in turn, led to a reduction of glucose uptake, lactate production, and glycolytic flux in HCC cells, and alteration of intracellular amino acid metabolome including glutamine, leucine, phenylalanine, tyrosine, and methionine.
Conclusions: Reintroduction of miR-148a-3p into HCC cells modulates glucose and amino acid metabolism via regulating multiple SLC transporters, thereby suppressing HCC cell viability. These findings highlight the role of miR-148a-3p in HCC cell metabolism and potential of bioengineered miRNA molecules for functional studies and therapeutic development.

Keywords:  Amino acids; Cell metabolism; Glucose; Hepatocellular carcinoma (HCC); MicroRNA-148a-3p (miR-148a-3p)

DOI:  https://doi.org/10.1016/j.livres.2026.04.001
Cancer Res. 2026 Jul 02. 86(13): 3106-3108

Forging New Pathways in Oncology: Strategic Insights from the 17th Annual Frontiers in Cancer Science Conference.

Dachuan Huang, Wee Wei Tee, Sanjay De Mel, Koji Itahana, Kanaga Sabapathy, Kristijan Ramadan, Reshma Taneja, Giang Le Minh, Derrick Sek Tong Ong, Zhong Yi Yeow, S Tiong Ong, Yilong Zhou, Anthony Khong, Soo-Chin Lee, Sasidharan Swarnalatha Lucky, Wai Leong Tam, N Gopalakrishna Iyer, Choon Kiat Ong.

The 17th Annual Frontiers in Cancer Science (FCS) conference (2025) highlighted the convergence of multiomics, computational biology, and ancestry-specific genomics to advance proactive cancer care. Key insights included the role of epigenetic plasticity in maintaining tumor-propagating states and the identification of metabolic vulnerabilities, such as the WNK1-mTORC1 axis in leukemia and MAF-driven glutamine metabolism in myeloma. The meeting underscored the systemic nature of cancer, detailing how "cancer-educated" neutrophils prime premetastatic niches and how spatial exclusion mechanisms hinder immunotherapy. Breakthroughs in therapeutic engineering were showcased, including CD7-directed chimeric antigen receptor T cells and irreversible KRASG12C inhibitors. A critical focus remained on precision oncology for diverse populations, advocating for ancestry-aware datasets and long-read sequencing to address genomic disparities in Asian cohorts. Furthermore, the integration of artificial intelligence-driven "fragmentomics" and machine learning offers new pathways for early detection and tracking disease lethality. Collectively, FCS 2025 demonstrated that the future of oncology lies in integrating high-resolution disease models with robust data science to transition from reactive treatment to personalized, interceptive management.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-1788
Biochim Biophys Acta Rev Cancer. 2026 Jun 28. pii: S0304-419X(26)00116-2. [Epub ahead of print]1881(4): 189644

Neural-tumor crosstalk in driving tumor metabolic reprogramming.

Xia Xiao, Congcong Zhang, Jiahao Chen, Jiayi Zhang, Hanyu Li, Weiming Yu, Xianlei Cai.

  Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.

Keywords:  Lactate; Metabolic reprogramming; Neural-tumor crosstalk; Neuro-immune-metabolic circuit; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2026.189644
Front Oncol. 2026 ;16 1837476

The multifaceted roles of mitochondria and their therapeutic transformation: a new perspective on triple-negative breast cancer treatment.

Siyuan Yang, Lei Wang, Jianyun Nie.

  Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, lacking effective targeted therapies and exhibiting pronounced therapeutic resistance. Mitochondria have recently emerged as central regulators of TNBC pathogenesis, functioning beyond their traditional roles as cellular powerhouses. This article synthesizes current understanding of how mitochondrial metabolic reprogramming-particularly the synergistic hyperactivation of oxidative phosphorylation, fatty acid oxidation, and glutamine metabolism-drives TNBC progression, metastasis, and chemoresistance. We further examine the dichotomous roles of mitochondrial dynamics and mitophagy in shaping tumor cell fate, and explore how mitochondria orchestrate diverse programmed cell death pathways and immune modulation. Translational strategies targeting mitochondrial vulnerabilities, including small-molecule inhibitors, nanomaterial-based delivery systems, and combination regimens, are critically evaluated. Despite significant preclinical promise, challenges including tumor selectivity, metabolic plasticity, and clinical translation remain. By integrating mechanistic insights with emerging therapeutic innovations, this perspective highlights the transformative potential of mitochondria-targeted interventions for future TNBC management.

Keywords:  mitochondria; mitochondria-targeted therapy; mitochondrial dynamics; mitochondrial metabolism; triple-negative breast cancer

DOI:  https://doi.org/10.3389/fonc.2026.1837476
Cell Biochem Funct. 2026 Jul;44(7): e70249

Redox Metabolism and Metabolic Vulnerabilities in Diabetes-Driven Pancreatic Cancer: Targeting System Xc-, mTORC1, and Disulfidptosis as Therapeutic Strategy.

Francis Jegan Raj, Anish Ruban Solomonraj, Parimelazhagan Thangaraj.

  Type 2 diabetes mellitus (T2DM) is increasingly recognized as a significant risk factor for pancreatic cancer, with both diseases sharing complex metabolic and molecular underpinnings. Insulin resistance, chronic inflammation, and aberrant activation of the KRAS-mTORC1 signaling axis collectively foster a tumor-permissive microenvironment and disrupt glucose regulation. Recent advances have highlighted disulfidptosis, a novel NADPH-depletion and disulfide-accumulation-driven cell death, as a therapeutic vulnerability in KRAS-mutated, cystine-dependent tumors. This process is linked to the metabolic interplay between glutamate/glutamine and cystine/cysteine, intersecting with mTORC1 signaling and GPX4 regulation. Key regulators, including system Xc-, GPX4, and GLUT, orchestrate the interplay between insulin resistance, redox imbalance, and oncogenic signaling in T2DM-associated pancreatic cancer. High expression of cystine/glutamate antiporters (system Xc-) promotes cystine accumulation and NADPH depletion, sensitizing tumor cells to disulfidptosis under glucose deprivation. Biomarker-guided precision medicine approaches leverage SLC7A11, GPX4, and p-mTOR expression to identify patient subsets vulnerable to dual metabolic-redox disruption. Emerging therapeutic strategies focus on restricting glucose availability or manipulating antiporters to induce disulfide stress. Integration of metabolic inhibitors with immune checkpoint inhibitors induces immunogenic cell death and overcomes the immunosuppressive pancreatic tumor microenvironment. Targeting these pathways may overcome therapy resistance and improve outcomes in KRAS- or mTOR-driven malignancies. This review synthesizes mechanistic and translational insights into the cyst(e)ine-mTORC1-GPX4 axis, glutaminolysis, biomarker-guided precision medicine, and disulfidptosis, offering a foundation for future therapeutic development in T2DM-associated pancreatic cancer.

Keywords:  Disulfidptosis; Metabolic reprogramming; Pancreatic Cancer; T2DM; Therapeutic resistance

DOI:  https://doi.org/10.1002/cbf.70249
Epigenomics. 2026 Jul 03. 1-11

HOTAIR at the metabolic crossroads: lncRNA control of carbohydrate and lipid metabolism.

Julio Sánchez-Pérez, Samuel Trujano-Camacho, Verónica García-Castillo, Mercedes Olvera-Valencia, David Cantú de León, Eduardo López-Urrutia, Carlos Pérez-Plasencia.

  Cancer cells reprogram their metabolic networks to sustain continuous proliferation, resist stress, and support invasive behavior. This metabolic rewiring includes enhanced aerobic glycolysis, increased glutaminolysis to fuel biosynthetic reactions, activation of the pentose phosphate pathway (PPP) for nucleotide synthesis and redox balance, and reorganization of lipid metabolism to integrate membrane biogenesis and energy adaptation. While several oncogenes are well established as metabolic regulators, it is increasingly recognized that non-coding RNAs also contribute to the control of tumor metabolic phenotypes. Among them, the long non-coding RNA (lncRNA) HOX transcript antisense intergenic RNA (HOTAIR) has emerged as one of the most consistently upregulated and functionally relevant lncRNAs in human cancers. Accumulating evidence links HOTAIR to metabolic reprogramming in diverse tumor types. HOTAIR controls the expression and activity of key glycolytic enzymes and regulates lipogenesis, lipid accumulation, and metastatic lipid remodeling. However, findings remain dispersed across individual studies, and a consolidated framework integrating HOTAIR regulation with major metabolic pathways is currently lacking. This review synthesizes current knowledge on how HOTAIR drives metabolic rewiring in cancer, with a focus on carbohydrate and lipid metabolism, and discusses the underlying molecular mechanisms and therapeutic implications.

Keywords:  Aberrant metabolism; HOTAIR; glutaminolysis; glycolysis; lipid metabolism; long non-coding RNAs

DOI:  https://doi.org/10.1080/17501911.2026.2691028
Anticancer Res. 2026 Jul;46(7): 3599-3608

Metabolic Reprogramming and Chemoresistance in Pancreatic Ductal Adenocarcinoma: Mechanisms and Therapeutic Strategies.

Dohee Ahn, Kyung-Chul Choi.

  Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with morbidity and mortality driven by late diagnosis, a dense desmoplastic stroma, and resistance to conventional therapies. Over sequential therapeutic eras, treatment has progressed from early cytotoxic agents to metabolism-directed strategies. A central feature of PDAC biology is extensive metabolic reprogramming, largely controlled by the Kirsten rat sarcoma viral oncogene homologue (KRAS) protein, which promotes aerobic glycolysis, glutamine utilization, and mitochondrial oxidative phosphorylation to sustain tumor growth under nutrient-limiting conditions. Accordingly, therapeutic efforts have increasingly focused on exploiting these metabolic dependencies, including inhibitors of glycolysis, glutaminase, and mitochondrial complex I, which have shown encouraging results in preclinical studies. Constitutively elevated autophagy-lysosomal flux provides PDAC cells with the capacity for nutrient recycling and supports immune evasion by promoting the neighbor of BRCA1 gene 1 (NBR1) protein-dependent degradation of major histocompatibility complex class I (MHC-I). Although inhibition of autophagy with hydroxychloroquine and related lysosomal inhibitors has provided proof of concept, their limited specificity has motivated the development of more selective approaches, such as Unc-51-like autophagy activating kinase 1 (ULK1) inhibitors and selective autophagy receptor-directed strategies. Emerging combination regimens that integrate autophagy blockade with KRAS/extracellular signal-regulated kinase (ERK) pathway inhibition, metabolic stress, or immune checkpoint blockade may help overcome chemoresistance and enhance anti-tumor immunity. Together, these advances underscore the therapeutic promise of targeting metabolic plasticity and autophagy in PDAC and lay the groundwork for rational next-generation combination strategies.

Keywords:  KRAS; Pancreatic ductal adenocarcinoma; metabolic reprogramming; resistance; review

DOI:  https://doi.org/10.21873/anticanres.18226
Front Pharmacol. 2026 ;17 1854265

Phillygenin suppresses hepatocellular carcinoma progression by modulating the TNF signaling pathway and TCA cycle metabolism.

Jiao Luo, Chang Liu, Yi Pang, Lianhong Pan.

   Background: Phillygenin (PLE) is a bioactive constituent of Forsythiae fructus that exerts hepatoprotective, anti-inflammatory, and antitumor effects. However, its role in hepatocellular carcinoma (HCC) and the mechanisms underlying its activity remain insufficiently characterized.
Methods: The effect of PLE on HCCLM3 and Hep3B tumor cells was assessed using immunofluorescence (IF) staining, TUNEL assay, qRT-PCR, and Western blotting experimental methodology. RNA-sequencing (RNA-seq) was used to detect changes in gene expression and to explore the gene targets and related pathways. Liquid chromatography-mass spectrometry (LC-MS) was used to identify the effects of PLE on primary metabolite targets and metabolism-related pathways. Tumor xenograft models were used for in vivo verification.
Results: PLE inhibited HCC cell proliferation through the inhibition of cell cycle progression and induction of cell apoptosis in vitro, indicating a dual antiproliferative and pro-apoptotic effect. These responses were associated with the modulation of the TNF signaling pathway. Moreover, PLE induced significant alterations in the central carbon metabolism, including the regulation of citrate synthesis and upregulation of oxoglutarate dehydrogenase (OGDH) expression in HCC cells. Finally, PLE treatment significantly reduced tumor growth in vivo, thereby confirming its therapeutic potential.
Conclusion: PLE exerts antitumor effects in HCC through the coordinated regulation of tricarboxylic acid (TCA) cycle metabolism while simultaneously inhibiting the TNF signaling pathway, highlighting its potential as a candidate antitumor drug for the treatment of HCC.

Keywords:  TNF signaling pathway; hepatocellular carcinoma; oxoglutarate dehydrogenase; phillygenin; tricarboxylic acid cycle

DOI:  https://doi.org/10.3389/fphar.2026.1854265
Exp Hematol Oncol. 2026 Jul 02.

Targeting the cancer metabolism-immunity interface: update and perspectives.

Emma Di Carlo.

  Metabolic crosstalk between cancer cells and immune cells is now recognized as a major determinant of immune escape and resistance to anticancer treatments. Cancer cells profoundly reshape the metabolic landscape of the tumor microenvironment, driving nutrient competition, hypoxia, and the accumulation of immunosuppressive oncometabolites that collectively blunt antitumor immunity. Effector T cells, NK cells, and dendritic cells are exposed to nutrient deprivation and suppressive metabolites, including lactate, adenosine, and kynurenine, resulting in impaired T cell proliferation and cytotoxic function and expansion of metabolically adapted regulatory T cells and myeloid-derived suppressor cells. Cancer-associated fibroblasts further reinforce this metabolic reprogramming through extracellular matrix remodeling, secretion of immunosuppressive metabolites, and nutrient recycling that supports tumor growth. Abnormal tumor vasculature sustains metabolic stress by causing uneven perfusion, hypoxia, and acidosis, thereby limiting immune cell infiltration, and promoting immune exhaustion. In addition, diet- and microbiome-driven metabolic cues dynamically shape cancer-immunity interactions and therapeutic responses. Targeting key metabolic checkpoints, including glycolysis, adenosine signaling, tryptophan metabolism, fatty acid oxidation, and lactate production, has emerged as a promising strategy to restore antitumor immunity. Nevertheless, metabolic heterogeneity, context-dependent immune responses, and safety concerns pose persistent challenges to its successful implementation. Recent advances in biomarker development, patient stratification, and rational combination strategies underpin the clinical translation of metabolic-immune vulnerabilities in cancer therapy. Integrating metabolic interventions with immune checkpoint blockade or adoptive cell therapies has demonstrated synergistic effects in preclinical and early clinical studies, enhancing T cell persistence and cytotoxic function within metabolically hostile tumor microenvironments. This review addresses these issues and delineates the mechanistic basis of the dynamic interplay between cancer metabolism and immune regulation. It discusses how anti-cancer therapies affect metabolic and immune pathways and highlights next-generation, metabolically targeted therapies that leverage newly uncovered, tumor-specific rewiring of glycolysis, mitochondrial function, and nutrient uptake. Special emphasis is given to the development of first-in-class inhibitors targeting glutaminase, lipid biosynthesis, one-carbon pathways, and redox homeostasis, which, when paired with immunotherapy or conventional treatments, offer unprecedented opportunities to overcome metabolic barriers, abrogate resistance, and achieve durable immune control of cancer.

Keywords:  Cancer-associated fibroblasts; Diet and cancer; Immune cell metabolism; Immunotherapy; Microbiome and cancer; Oncometabolites; Therapy resistance; Tumor metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-026-00776-2