Metabolic Crosstalk in the Tumor Microenvironment

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

Deadline for manuscript submissions: 31 July 2026 | Viewed by 2209

Special Issue Editors


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Guest Editor
Group for Hematology and Stem Cells, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia
Interests: stem cells; cancer; multiple myeloma; cell metabolism; bone marrow
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Guest Editor
Group for Immunology, Institute for Medical Research, National Institute of the Republic of Serbia, University of Belgrade, 11029 Belgrade, Serbia
Interests: cancer; melanoma; oxidative stress; cell signaling

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Guest Editor
Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade; Center of Excellence for Redox Medicine, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia
Interests: laboratory diagnostics in oncology; urological cancers; redox medicine; metabolism

Special Issue Information

Dear Colleagues,

The dynamic metabolic interactions in the tumor microenvironment (TME) are pivotal in driving tumor progression, immune evasion, and therapeutic resistance in solid and hematological malignancies. These interactions involve crosstalk between cancer cells and stromal cells (e.g., cancer-associated fibroblasts, endothelial cells, and immune cells) mediated by nutrient competition, metabolic symbiosis, and signaling metabolites. Defining metabolic crosstalk between cancer cells and TME is of paramount importance for advancement in cancer prediction, diagnosis, and therapy.

Oncometabolites, together with the altered activity of essential metabolic enzymes, are important mediators of cancer growth, immune evasion, and metastasis. Molecules including lactate, succinate, fumarate, and D-2 hydroxyglutarate (D-2HG) act as drivers of cancer by altering epigenetic regulation, impairing DNA repair, and remodeling the TME, linking genetic alterations to metabolic and epigenetic dysregulation in cancer. This profiling serves as a powerful tool for cancer biomarker discovery, understanding tumor biology, and guiding precision oncology interventions.

This Special Issue will include research articles and reviews that aim to elucidate a new interplay between cancer cells and TME metabolism. Articles within this issue should address the multifaceted nature of TME metabolism, tackling the scientific challenges of the metabolic reprogramming (altered macromolecule metabolism, redox balance, and adaptation to hypoxia), metabolic crosstalk between tumor and stromal cells, nutrient competition, immune response modulation, etc. Further, the issue explores emerging therapeutic strategies that target metabolic key points within the TME to disrupt tumor progression and enhance the efficacy of existing treatments. Through a multidisciplinary approach, this Special Issue provides a comprehensive overview of the metabolic landscape of the TME, offering new insights and potential avenues for cancer therapy.

Articles should contain one of the following:

  • Nutrient competition and scarcity in the interplay between tumor cells and TME;
  • Symbiotic metabolite exchange between tumor cells and TME cells;
  • Immunosuppressive metabolites: Lactate, adenosine, and tryptophan;
  • Age-related metabolic reprogramming of TME: Oncometabolites and epigenetic changes;
  • Targeting metabolic pathways and oncometabolites: Diagnostic and therapeutic opportunities;
  • Integrative omics technologies in revealing tumor metabolites.

Dr. Drenka Trivanovic
Dr. Ristic Biljana
Dr. Vesna M. Ćorić
Guest Editors

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Keywords

  • cancer
  • oncometabolites
  • tumor microenvironment
  • metabolic crosstalk

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Published Papers (2 papers)

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Research

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21 pages, 10978 KB  
Article
Integrating Transcriptomics and 3D Spheroid Models Reveals Microenvironment-Dependent Purinergic Modulation in Hepatocellular Carcinoma
by Arieli Cruz de Sousa, Augusto Ferreira Weber, Vinícius Klain, Juliete Nathali Scholl, Jéssica Marques Obelar Ramos, Natália Baltazar do Nascimento, Maria Luiza Giehl, Renata Kruger Martins, João Vitor Heres, Camila Kehl Dias, Renata Marschner, Fabrício Figueiró and Fátima Costa Rodrigues Guma
Metabolites 2026, 16(3), 152; https://doi.org/10.3390/metabo16030152 - 25 Feb 2026
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Abstract
Background/Objectives: Dysregulation of purinergic signaling, particularly CD73 overexpression, influences tumor progression, immune evasion, and chemoresistance in hepatocellular carcinoma (HCC). We aimed to characterize the transcriptional landscape of this system, identify prognostic markers, and investigate how the tumor microenvironment modulates pharmacological response to [...] Read more.
Background/Objectives: Dysregulation of purinergic signaling, particularly CD73 overexpression, influences tumor progression, immune evasion, and chemoresistance in hepatocellular carcinoma (HCC). We aimed to characterize the transcriptional landscape of this system, identify prognostic markers, and investigate how the tumor microenvironment modulates pharmacological response to combined sorafenib and doxazosin in 3D spheroid models. Methods: We integrated RNA-seq data from The Cancer Genome Atlas—Liver Hepatocellular Carcinoma (TCGA-LIHC) to identify differentially expressed genes, pathway enrichment, gene co-expression networks, prognostic associations, and machine learning-based biomarker selection. Modulation of key targets was assessed in HepG2 and HepG2/LX-2 spheroids treated with sorafenib and doxazosin using qPCR and flow cytometry. Results: Transcriptomics revealed dysregulation and network fragmentation. Specifically, analysis of the TCGA cohort indicated that high expression of ADA, NT5E, and ADORA1 correlated with poor overall survival. Given the critical role of CD73 in therapy resistance, we evaluated these findings in 3D models. Co-treatment significantly downregulated NT5E and ADORA1 mRNA expression, while ADORA2A was specifically reduced in the co-culture setting. For the ADA, effect-size analysis revealed a large magnitude of inhibition in HepG2 spheroids. Although flow cytometry showed that high CD73 protein expression remained stable across treatments in co-culture, the combination therapy overcame stromal protection, significantly increasing apoptosis (active caspase-3) in both mono- and co-culture spheroids compared with vehicle and monotherapy. Conclusions: We identified a purinergic prognostic signature in HCC and demonstrated that the combination therapy of sorafenib and doxazosin targets the adenosine pathway and specific receptors. We show that the stromal microenvironment sustains CD73 protein expression even under transcriptional inhibition, highlighting the critical role of 3D co-culture models in deciphering therapeutic resistance mechanisms. Full article
(This article belongs to the Special Issue Metabolic Crosstalk in the Tumor Microenvironment)
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Review

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19 pages, 776 KB  
Review
Lipoprotein Metabolism in Hematological Malignancies: A Role in Shaping the Tumor Cell Microenvironment?
by Manal Sellam, Mélanie Lambert, Nadine Varin-Blank and Kevin Saitoski
Metabolites 2026, 16(2), 145; https://doi.org/10.3390/metabo16020145 - 20 Feb 2026
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Abstract
The tumor microenvironment (TME) plays a key role in driving tumor progression, metastasis, and resistance to therapy. The TME is a highly variable ecosystem composed of both cancer and surrounding normal cells, immune survey cells and the extracellular matrix, also composed of signaling [...] Read more.
The tumor microenvironment (TME) plays a key role in driving tumor progression, metastasis, and resistance to therapy. The TME is a highly variable ecosystem composed of both cancer and surrounding normal cells, immune survey cells and the extracellular matrix, also composed of signaling molecules that mediate interactions between them. Blood cancer cells pose a unique challenge because of their circulation and widespread distribution along with their capacity to invade various niches, interacting with a wide range of host cells such as fibroblasts, immune cells, endothelial cells, and adipocytes. Metabolism reprogramming in this tumor context, notably referring to elevated cholesterol and fatty acid metabolism, emerges as a crucial event in shaping an immune-suppressive microenvironment that promotes tumor progression. Cholesterol and fatty acids are supplied by both de novo biosynthesis and exogenous uptake from lipoproteins. Lipoproteins are pseudo-micellar structures, designed to transport essential water-insoluble metabolites, including triacylglycerols and cholesterol, in the plasma, lymph, and interstitial fluids. A number of studies have reported abnormal circulating lipoprotein levels in leukemic patients and have suggested that lipoproteins are key for cancer cells to thrive. However, the role of lipoprotein metabolism in cancer cells in the context of the TME is still incompletely discussed so far. The aim of this review is to consider the importance of lipoprotein metabolism in shaping the tumor microenvironment in the context of hematological malignancies. Full article
(This article belongs to the Special Issue Metabolic Crosstalk in the Tumor Microenvironment)
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