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Metabolites
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Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment
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Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: 5 July 2026 | Viewed by 6989

Special Issue Editor

Dr. Jyoti Kaushal

E-Mail Website
Guest Editor
Mayo Clinic Arizona, Scottsdale, AZ 85259, USA
Interests: cancer research; tumor microenvironment; therapeutics; molecular signaling; cellular biochemistry; cell death mechanism; cancer metastasis; metabolism; ciliary pathways; endocrinology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

Metabolic reprogramming within the tumor microenvironment (TME) is a prominent area of research due to its effects on cancer progression, therapy resistance, and the development of new therapeutic targets. The TME is characterized by altered metabolic properties where the different cell subsets, including malignant cells, stromal cells, immune cells, and endothelial cells, affect tumor growth and immune responses. Malignant cells adapt through symbiotic metabolic interactions with other tumor cells to reshape the TME and often shift towards glycolysis (the Warburg effect) or modify fatty acid metabolism. This metabolic switch influences their interaction with surrounding tissues that support tumor growth, immune evasion, and angiogenesis. Meticulously regulated metabolic pathways and their shifting in the TME have become a key focus of the current research, offering promising opportunities for therapeutic targeting and improving preclinical and clinical outcomes.

This Special Issue will feature reviews and original research articles on cutting-edge methods for metabolic profiling in TME, with applications in pathological conditions. It will emphasize studies on metabolomic pathways and their impact on tumor heterogeneity, cell-type switching, peri-neural invasion, and crosstalk molecular mechanism, all with implications for clinical oncology, employing diverse analysis platforms. Therapy resistance remains a critical concern in the field of cancer biology. Additionally, we will highlight how metabolic changes across cells within the TME can impact immune or non-immune cell function, potentially impacting the efficacy of therapies for both cold and hot tumors. Consequently, research that employs metabolomic shifting and related mechanistic insights to understand tumor progression, disease advancement, and drug resistance with the potential to uncover new drug targets will be prioritized.

Dr. Jyoti Kaushal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metabolism
  • tumor microenvironment
  • therapy
  • immune cells
  • clinical oncology
  • metabolic pathways

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Published Papers (5 papers)

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Research

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20 pages, 2382 KB  
Article
Hypoxia Dependent Inhibition of Glioblastoma Cell Proliferation, Invasion, and Metabolism by the Choline-Kinase Inhibitor JAS239
by Claire Louise Kelly, Martyna Wydrzynska, Marie M. Phelan, Sofya Osharovich, Edward J. Delikatny, Violaine Sée and Harish Poptani
Metabolites 2025, 15(2), 76; https://doi.org/10.3390/metabo15020076 - 26 Jan 2025
Cited by 1 | Viewed by 1982
Abstract
Background: Elevated choline kinase alpha (ChoK) levels are observed in most solid tumors, including glioblastomas (GBM), and ChoK inhibitors have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with resistance to GBM therapy, we hypothesized that tumor hypoxia could be [...] Read more.
Background: Elevated choline kinase alpha (ChoK) levels are observed in most solid tumors, including glioblastomas (GBM), and ChoK inhibitors have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with resistance to GBM therapy, we hypothesized that tumor hypoxia could be responsible for the limited response. Therefore, we evaluated the effects of hypoxia on the function of JAS239, a potent ChoK inhibitor in four GBM cell lines. Methods: Rodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 h of hypoxic conditioning and treated with JAS239 for 24 h. NMR metabolomic measurements and analyses were performed to evaluate the signaling pathways involved. In addition, cell proliferation, cell cycle progression, and cell invasion parameters were measured in 2D cell monolayers as well as in 3D cell spheroids, with or without JAS239 treatment, in normoxic or hypoxic cells to assess the effect of hypoxia on JAS239 function. Results: Hypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways, associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, effects from JAS239 were variable depending on the cell line, reflecting the inherent heterogeneity of GBMs. Conclusions: Our findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit cell proliferation, and alter cell invasion. These results may be useful for designing new therapeutic strategies based on ChoK inhibition, which can act on multiple pro-tumorigenic features. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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Review

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18 pages, 829 KB  
Review
Nexus of IDO1/Kynurenine Pathway to T-Cell Exhaustion: Hypoxia-Induced Tryptophan Metabolism in Glioblastoma
by Matthew Abikenari, George Nageeb, Joseph H. Ha, Matthew Adam Sjoholm, Justin Liu, Brandon Bergsneider, Jocelyn Valenzuela, James Poe, Kwang Bog Cho, Rohit Verma, Caren Wu, Vivek Sanker, Ravi Medikonda, Lily H. Kim, John Choi, Matei A. Banu and Michael Lim
Metabolites 2026, 16(3), 185; https://doi.org/10.3390/metabo16030185 - 10 Mar 2026
Cited by 1 | Viewed by 1773
Abstract
Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the [...] Read more.
Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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12 pages, 406 KB  
Review
The Significance of the Heterogeneity of Cancer-Associated Fibroblasts in Tumor Microenvironments
by Daiki Imanishi, Hinano Nishikubo, Dongheng Ma, Hongdong Gao, Tomoya Sano, Canfeng Fan, Takashi Sakuma, Yurie Yamamoto and Masakazu Yashiro
Metabolites 2026, 16(2), 120; https://doi.org/10.3390/metabo16020120 - 9 Feb 2026
Viewed by 715
Abstract
The tumor heterogeneity that is frequently observed in cancer tissues comprises not only cancer cells but also stromal cells in the tumor microenvironment. One of the major components of tumor stroma, i.e., cancer-associated fibroblasts (CAFs), play crucial roles in tumor progression and the [...] Read more.
The tumor heterogeneity that is frequently observed in cancer tissues comprises not only cancer cells but also stromal cells in the tumor microenvironment. One of the major components of tumor stroma, i.e., cancer-associated fibroblasts (CAFs), play crucial roles in tumor progression and the tumor response to chemotherapy. The known subtypes of CAFs are antigen-presenting CAFs (apCAFs), myofibroblastic CAFs (myCAFs), and inflammatory CAFs (iCAFs). It has been speculated that (i) the heterogeneity of CAF subtypes might contribute to tumor progression; (ii) cell-to-cell interactions among CAF subtypes in tumors might be associated with the development of various types of carcinomas, and (iii) juxtracrine and/or paracrine signaling from CAFs may play important roles in this development. A clarification of the mechanisms that underlie the tumoral heterogeneity of CAFs could contribute to cancer treatment as precision medicine. This review explains the significance of CAF heterogeneity in tumor microenvironments, especially concerning the CAF subtypes. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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20 pages, 1028 KB  
Review
Lactic Acid in Tumour Biology
by Cristina Cruz and Ignasi Barba
Metabolites 2026, 16(1), 75; https://doi.org/10.3390/metabo16010075 - 15 Jan 2026
Cited by 1 | Viewed by 1274
Abstract
Lactic acid accumulates in the tumour microenvironment (TME) at concentrations reaching up to 40 mM. Initially, lactic acid was considered merely a metabolic by-product of aerobic glycolysis, a phenomenon commonly referred to as the Warburg effect and observed in the majority of tumours. [...] Read more.
Lactic acid accumulates in the tumour microenvironment (TME) at concentrations reaching up to 40 mM. Initially, lactic acid was considered merely a metabolic by-product of aerobic glycolysis, a phenomenon commonly referred to as the Warburg effect and observed in the majority of tumours. Recent evidence, however, has demonstrated that lactic acid is not merely a waste product; rather, it plays a pivotal role in tumour biology. High plasma lactic acid levels correlate with increased metastatic potential and lower survival rates. Elevated lactic acid levels in the TME have been shown to suppress antitumour immune responses, facilitate both metastasis and cellular senescence, and might modulate gene expression through novel epigenetic mechanisms such as histone lactylation. This review aims to summarize current knowledge on the multifaceted impact of elevated lactic acid in the TME on tumour progression and biology. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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Other

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19 pages, 2480 KB  
Systematic Review
Circulating Lipid Traits and Ovarian Cancer Risk: A Systematic Review and Meta-Analysis with Mendelian Randomization Integration
by Marco Marian, Andrei Ardelean, Mihai Rosu, Cristi Tarta, Alexandru Isaic, Dan Brebu, Camelia Marian, Ioana Adelina Faur, Paul Pasca, Ionut Flaviu Faur, Dana Stoian and Andrei Korodi
Metabolites 2026, 16(5), 290; https://doi.org/10.3390/metabo16050290 - 23 Apr 2026
Viewed by 264
Abstract
Background: Metabolic dysregulation is increasingly recognized as a contributor to carcinogenesis; however, the role of circulating lipid traits in ovarian cancer remains unclear. Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Web of Science, Scopus, and [...] Read more.
Background: Metabolic dysregulation is increasingly recognized as a contributor to carcinogenesis; however, the role of circulating lipid traits in ovarian cancer remains unclear. Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Web of Science, Scopus, and Embase were searched from inception to March 2026. Observational studies evaluating triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) in relation to ovarian cancer risk were included. Random-effects models were used to pool relative risks (RRs). Robustness was assessed via sensitivity analyses, influence diagnostics, and multiverse analysis. Mendelian randomization (MR) evidence was integrated for causal inference. Results: Six observational studies were included in the meta-analysis. Elevated triglyceride levels were associated with increased ovarian cancer risk, while HDL-C showed a modest inverse association. LDL-C and total cholesterol were not significantly associated with risk. Sensitivity analyses excluding early follow-up strengthened the triglyceride association. MR analyses supported a potential causal role for triglycerides but not for HDL-C. Conclusions: Circulating triglycerides may represent a metabolically relevant risk factor for ovarian cancer. Further large-scale prospective and mechanistic studies are warranted. Full article
(This article belongs to the Special Issue Mechanistic Insights into Metabolic Interactions with the Tumor Microenvironment)
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