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Metabolites
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Metabolic Reprogramming in Cancer: New Frontiers for Therapeutic Intervention
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Metabolic Reprogramming in Cancer: New Frontiers for Therapeutic Intervention

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

Deadline for manuscript submissions: closed (31 December 2025) | Viewed by 2366

Special Issue Editors

Dr. Songhua Hu

E-Mail Website
Guest Editor
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
Interests: metabolite signaling; mitochondrial metabolism
Dr. Yahui Wang

E-Mail Website
Guest Editor
Department of Oncology, Johns Hopkins University, Baltimore, MD 21287, USA
Interests: cancer metabolism; LC/MS-based metabolomics; nutrition
Dr. Daniel Oscar Cicero

E-Mail Website
Guest Editor
Department of Chemical Science and Technology, Università degli Studi di Roma Tor Vergata, 1, 00133 Rome, Italy
Interests: nuclear magnetic resonance; metabolomics; bladder cancer; cardiovascular diseases; metabolism and exercise
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer cells rewire metabolism to support their needs for survival, growth, and proliferation. This metabolic rewiring is now recognized as a hallmark feature of cancer cells and has unveiled promising opportunities for developing novel therapies. Despite this promise, however, the metabolic plasticity and heterogeneity in cancer cells present ongoing challenges. Cancer cells can adapt their metabolic pathways to environmental changes and therapeutic pressures, leading to treatment resistance and disease progression. As such, further exploration and understanding of the underlying mechanisms driving metabolic reprogramming in cancer is necessary.

In this Special Issue, we aim to cover the recent progress in cancer therapy by targeting cancer metabolism. We hope to pave the way for innovative and effective therapeutic strategies by addressing the complexities of metabolic plasticity and heterogeneity in cancer cells. The topics include, but are not limited to, the following: 

(i) Molecular mechanisms underlying metabolic adaptability in therapeutic resistance;

(ii) Metabolic heterogeneity in cancer;

(iii) Determination of how tumor microenvironment, such as hypoxia and nutrient availability, influence cancer metabolism;

(iv) Development of novel therapies and combination strategies to improve therapeutic efficacies and clinical outcomes.

We seek original research articles, reviews, and short communications and invite researchers, clinicians, and industry professionals to contribute their insights and findings to advance our understanding of cancer metabolism and its application in clinical practice.

Dr. Songhua Hu
Dr. Yahui Wang
Dr. Daniel Oscar Cicero
Guest Editors

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

  • cancer metabolism
  • metabolic reprogramming
  • metabolic plasticity
  • cancer heterogeneity
  • therapeutic resistance
  • tumor microenvironment
  • combination therapies

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Published Papers (2 papers)

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Research

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14 pages, 1545 KB  
Article
CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells
by Didem Agac Cobanoglu, Samantha Franklin, Yue Hu, Devon J. Boland and Xiaotong Song
Metabolites 2026, 16(1), 52; https://doi.org/10.3390/metabo16010052 - 7 Jan 2026
Viewed by 716
Abstract
Background/Objectives: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even [...] Read more.
Background/Objectives: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways. Methods: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming. Results: All CAR T cells exhibited activation of NF-κB–centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes. Conclusions: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Cancer: New Frontiers for Therapeutic Intervention)
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Review

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22 pages, 723 KB  
Review
NHE1-Mediated Metabolic Reprogramming in Cancer
by Majd A. Al-Hamaly, Beau R. Forester and Jessica S. Blackburn
Metabolites 2026, 16(3), 195; https://doi.org/10.3390/metabo16030195 - 15 Mar 2026
Viewed by 904
Abstract
The sodium–hydrogen exchanger-1 (NHE1) is a ubiquitously expressed transmembrane transporter that plays a central role in maintaining intracellular pH homeostasis and supporting normal cellular function. In cancer, NHE1 is overexpressed in many tumor types and has been associated with increased cancer cell metastasis [...] Read more.
The sodium–hydrogen exchanger-1 (NHE1) is a ubiquitously expressed transmembrane transporter that plays a central role in maintaining intracellular pH homeostasis and supporting normal cellular function. In cancer, NHE1 is overexpressed in many tumor types and has been associated with increased cancer cell metastasis and proliferation. Beyond these established roles, emerging evidence implicates NHE1 as a regulator of cancer cell metabolism. By driving intracellular alkalinization and shaping the tumor microenvironment, NHE1 influences metabolic pathway activity, mitochondrial function, redox balance, and cellular stress responses. In this review, we synthesize current evidence linking NHE1 dysregulation to metabolic reprogramming in cancer, with a focus on mitochondrial metabolism, glycolytic flux, lysosomal biology, and reactive oxygen species-associated stress pathways. We further evaluate pharmacological strategies targeting NHE1, emphasizing their metabolic consequences, translational potential, and the challenges that have limited clinical application to date. Collectively, this review highlights NHE1 as a potential integrator of ion transport and metabolic control in cancer and discusses how targeting NHE1-driven metabolic programs may support the development of novel therapeutic strategies. Full article
(This article belongs to the Special Issue Metabolic Reprogramming in Cancer: New Frontiers for Therapeutic Intervention)
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