Overview of Cancer Metabolism

Topic Information

Dear Colleagues,

Cancers are characterized by a high metabolic heterogeneity, allowing cancer cells to survive and proliferate in harsh microenvironmental conditions, including hypoxia, acidosis, and limited availability of metabolic resources. In recent years, a growing body of experimental and clinical evidence has been obtained, suggesting that the metabolic plasticity of malignant cells plays a key role in cancer progression. Indeed, metabolic activities of cancer cells directly influence (epi)genetic modifications, intra- and inter-cellular signaling, metastatic processes, immune escape, and response of tumors to different anticancer therapies. Recent technical developments have allowed us to reveal the spatially and temporally resolved complexity of the metabolic networks within tumors and their role in tumor initiation and progression.

The aim of this Topic is to present new reports that advance our knowledge on tumor metabolism. We welcome the submissions of original research articles and reviews that focus on all aspects of cancer cell metabolism, with a special focus on the interactions between cancer cells and their microenvironment, as well as on the alterations of the various hallmarks of cancer. Apart from the contributions of conference participants, manuscripts are welcome from other interested research groups. All manuscripts will be peer-reviewed.

Dr. Arnaud Blomme
Dr. Cyril Corbet
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cancers cancers	4.4	8.8	2009	19.1 Days	CHF 2900
Cells cells	5.2	10.5	2012	15.5 Days	CHF 2700
Metabolites metabolites	3.7	6.9	2011	16.7 Days	CHF 2700
Organoids organoids	-	-	2022	27.8 Days	CHF 1200
Pathophysiology pathophysiology	2.6	4.6	1994	27.8 Days	CHF 1500

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Published Papers (7 papers)

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All Cells Organoids Cancers Metabolites Pathophysiology

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23 pages, 1887 KB  

Open AccessArticle

Activation of TAS2R Signaling by Diphenidol Suppresses Tumor Growth and Remodels the Tumor Immune Microenvironment in Oral Squamous Cell Carcinoma

by Nisrina Ekayani Nasrun, Akihiko Tanimura, Koki Yoshida, Osamu Uehara, Yuki Kunisada, Kiyofumi Takabatake, Akihiro Hosoya, Hiroaki Takebe, Hitoshi Nagatsuka, Yoshihiro Abiko, Muhammad Ruslin and Tsuyoshi Shimo

Cancers 2026, 18(10), 1527; https://doi.org/10.3390/cancers18101527 - 9 May 2026

Viewed by 271

Abstract

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, [...] Read more.

Background: Oral squamous cell carcinoma (OSCC) remains a clinically challenging malignancy characterized by aggressive behavior and limited therapeutic options. Bitter taste receptors (TAS2Rs), expressed across multiple tissues and cancer types, have recently emerged as regulators of tumor biology and immune responses; however, their functional significance in OSCC remains poorly understood. Methods: Immunohistochemical analysis was performed using surgically resected human tongue OSCC specimens and a tissue microarray (TMA) cohort. In parallel, four TAS2R agonists were evaluated in SCC7 cells to assess intracellular calcium responses. RNA sequencing was conducted to analyze transcriptional changes following diphenidol treatment, and functional assays, including proliferation, migration, and apoptosis analyses, were performed in vitro. Antitumor effects were further evaluated in a syngeneic SCC7 mouse model, followed by TUNEL staining and flow cytometry to assess apoptosis and immune cell infiltration. Results: TAS2R38 expression was markedly upregulated in dysplastic and invasive OSCC lesions with predominant nuclear localization and was associated with histological grade and clinical stage, indicating an early and sustained alteration during tumor progression. Among the agonists tested, diphenidol most strongly induced IP₃-dependent intracellular Ca²⁺ elevation. RNA sequencing revealed upregulation of Il1rl1 and Lzts2. Functionally, diphenidol significantly suppressed SCC7 cell proliferation and migration and induced apoptosis in vitro. In vivo, diphenidol reduced tumor volume and weight and increased apoptotic activity. Flow cytometry demonstrated a marked reduction in tumor-infiltrating CD4⁺CD25⁺Foxp3⁺ regulatory T cells, indicating modulation of the tumor immune microenvironment. Conclusions: TAS2R activation by diphenidol suppresses tumor growth through both tumor-intrinsic mechanisms and modulation of the tumor immune microenvironment in OSCC. These findings define TAS2R-mediated calcium signaling as a novel axis linking tumor progression and immunoregulation. Given that diphenidol is a clinically approved drug with an established safety profile, our results provide a strong rationale for TAS2R-targeted drug repurposing strategies in cancer therapy. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

49 pages, 4235 KB  

Open AccessReview

Nanoparticle-Induced Breast Cancer Cell Death: The Associated Mechanisms of Seven Major Cell Death Pathways in Preclinical Models and a Cross-Validation Model

by Shirui Wang, Cuicui Chang, Rui Xu, Lizhou Wang, Bocheng Gao, Yuyang Yan, Yanju Gong and Yulin Li

Cells 2026, 15(7), 589; https://doi.org/10.3390/cells15070589 - 26 Mar 2026

Viewed by 1063

Abstract

Breast cancer is among the most common forms of cancer in women worldwide and continues to be a major challenge in medical science and clinical care because of the complexity of its biological nature and common resistance to treatment. Nanoparticles for treating breast [...] Read more.

Breast cancer is among the most common forms of cancer in women worldwide and continues to be a major challenge in medical science and clinical care because of the complexity of its biological nature and common resistance to treatment. Nanoparticles for treating breast cancer are becoming a new-generation approach to induce the death of breast cancer cells because of their favorable physicochemical properties and excellent targeting ability. Recent studies have shown that nanoparticles can significantly increase anticancer activity by activating several cell death mechanisms, such as pyroptosis, apoptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and disulfidptosis. The present review focuses on the molecular processes that lead to cell death in breast cancer models due to nanoparticle exposure. Such mechanisms have also been documented in other solid tumors, suggesting the possible universality of the cell death induced by nanoparticles. In the current review, we systematically summarize the molecular mechanisms underlying the various forms of cell death caused by nanoparticles in breast cancer cells to provide a theoretical background for the translational use of nanotechnology in precise breast cancer treatment and a cross-validation model for future mechanistic research on various types of cancer. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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19 pages, 1643 KB  

Open AccessArticle

Stefin B and Cystatin C Deficiency Suppresses Tumor Growth and Alters Tumor Microenvironment in a Breast Cancer Model

by Petra Matjan Štefin, Janja Završnik, Miha Butinar, Georgy Mikhaylov, Boris Turk and Olga Vasiljeva

Cells 2026, 15(4), 360; https://doi.org/10.3390/cells15040360 - 17 Feb 2026

Viewed by 714

Abstract

Background/Objectives: Cysteine cathepsins and their endogenous inhibitors have been shown to possess context-dependent functions in cancer progression, including the regulation of tumor metabolic pathways. Stefin B and cystatin C, intracellular and extracellular protease inhibitors, respectively, can modulate tumor biology through protease-dependent and [...] Read more.

Background/Objectives: Cysteine cathepsins and their endogenous inhibitors have been shown to possess context-dependent functions in cancer progression, including the regulation of tumor metabolic pathways. Stefin B and cystatin C, intracellular and extracellular protease inhibitors, respectively, can modulate tumor biology through protease-dependent and protease-independent mechanisms. This study investigated their combined functions and potential roles as tumor promoters in breast cancer in a spontaneous breast cancer mouse model (PyMT mice). Methods: We generated PyMT transgenic mice lacking both stefin B and cystatin C (double-knockout, DKO) and compared their tumor growth kinetics, proliferation, apoptosis, and metastatic burden with those of wild-type control mice. Immunohistochemistry was performed to characterize tumor macrophage infiltration and polarization. Results: DKO mice demonstrated delayed tumor onset, significantly slower tumor growth, reduced proliferation, increased apoptosis, and fewer lung metastases compared to wild-type controls. Immunohistochemistry revealed enhanced macrophage infiltration of the tumors, accompanied by a pronounced shift toward antitumorigenic M1 (CD86⁺) polarization, while M2 (CD206⁺) populations remained unchanged, indicating an immunological reprogramming of the tumor microenvironment toward a pro-inflammatory, tumor-suppressive state. Conclusions: Our results demonstrated a potential function of stefin B and cystatin C as tumor promoters in breast cancer through complementary mechanisms. Simultaneous depletion of both inhibitors revealed synergistic effects and remodeled the immune microenvironment to favor tumor suppression. These results suggest previously unknown roles for stefin B and cystatin C in tumor development and progression, which encourage further investigation of the cancer metabolic mechanisms underlying tumor behavior and their dynamic interplay with the microenvironment. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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34 pages, 472 KB  

Open AccessReview

Lifestyle-Based Approaches to Cancer Prevention and Treatment: Diet, Physical Activity, and Integrative Strategies

by Gianpiero Greco, Alessandro Petrelli, Francesco Fischetti and Stefania Cataldi

Pathophysiology 2025, 32(4), 70; https://doi.org/10.3390/pathophysiology32040070 - 17 Dec 2025

Cited by 3 | Viewed by 3530

Abstract

Cancer remains a leading global cause of morbidity and mortality. Modifiable lifestyle factors, including avoidance of tobacco use and excessive ultraviolet radiation, healthy dietary patterns, regular physical activity, and weight management, play key roles in prevention and care. This narrative review synthesizes evidence [...] Read more.

Cancer remains a leading global cause of morbidity and mortality. Modifiable lifestyle factors, including avoidance of tobacco use and excessive ultraviolet radiation, healthy dietary patterns, regular physical activity, and weight management, play key roles in prevention and care. This narrative review synthesizes evidence on lifestyle-based interventions influencing cancer risk, treatment tolerance, and survivorship. A literature search was conducted in PubMed and Scopus, supplemented by manual screening via Google Scholar. The time frame (2001–2025) was selected to reflect evidence produced within the modern era of molecular oncology and contemporary lifestyle medicine research. Eligible publications addressed carcinogen exposure (tobacco, alcohol, ultraviolet radiation), diet and nutritional strategies, physical activity, sedentary behavior, obesity, metabolic health, complementary therapies, and cancer outcomes. Evidence indicates that reducing exposure to tobacco and ultraviolet radiation remains central to cancer prevention. Adherence to predominantly plant-based diets, regular physical activity, and maintenance of healthy body weight are consistently associated with lower incidence of several cancers, including breast, colorectal, and liver cancer. Nutritional strategies such as caloric restriction, ketogenic diets, and fasting-mimicking diets show promise in improving treatment efficacy and quality of life. Complementary and mind–body therapies may alleviate treatment-related symptoms, although high-quality evidence on long-term safety and effectiveness is limited. Integrating lifestyle medicine into oncology offers a cost-effective, sustainable strategy to reduce cancer burden and enhance survivorship. Comprehensive programs combining carcinogen avoidance, dietary regulation, structured exercise, and effective radiation risk mitigation may extend healthspan, improve treatment tolerance, and help prevent recurrence. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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28 pages, 586 KB  

Open AccessReview

A New Look at the Role of Radiation-Related Epigenetic Mechanisms in Diagnosis and Anticancer Therapies

by Adam Jan Olichwier, Magdalena Bruzgo-Grzybko, Izabela Suwda Kalita, Natalia Bielicka, Ewa Chabielska and Anna Gromotowicz-Poplawska

Cells 2025, 14(23), 1885; https://doi.org/10.3390/cells14231885 - 27 Nov 2025

Cited by 1 | Viewed by 1587

Abstract

Epigenetics encompasses heritable but reversible modifications of gene expression that occur without changes in the DNA sequence and involve mechanisms such as DNA and RNA methylation and histone modifications. These mechanisms modulate chromatin architecture, genome stability, and cellular responses to environmental stressors, and [...] Read more.

Epigenetics encompasses heritable but reversible modifications of gene expression that occur without changes in the DNA sequence and involve mechanisms such as DNA and RNA methylation and histone modifications. These mechanisms modulate chromatin architecture, genome stability, and cellular responses to environmental stressors, and their dysregulation contributes to oncogenesis and cancer progression. In parallel, radiotherapy remains a cornerstone of cancer treatment; furthermore, ionizing radiation induces epigenetic modifications alongside direct DNA double-strand breaks and oxidative damage. Radiation-induced epigenetic changes, including global or locus-specific DNA methylation shifts (e.g., genes promoter CpG islets), histone acetylation and methylation imbalances, are increasingly recognized as key contributors to molecular radioresistance. These adaptive responses may enhance tumor cell survival, affect therapeutic efficacy, and promote metastasis. Understanding the interplay between radiation exposure and epigenetic remodeling opens new perspectives for precision oncology and diagnostics. Epigenetic biomarkers hold potential for predicting treatment response and prognosis, while epigenetic modifiers may sensitize tumors to radiation. This review summarizes current evidence on radiation-induced epigenetic mechanisms and evaluates their diagnostic, prognostic, and therapeutic implications in cancer management. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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38 pages, 1308 KB  

Open AccessReview

Mitochondrial Metabolomics in Cancer: Mass Spectrometry-Based Approaches for Metabolic Rewiring Analysis and Therapeutic Discovery

by Yuqing Gao, Zhirou Xiong and Xinyi Wei

Metabolites 2025, 15(8), 513; https://doi.org/10.3390/metabo15080513 - 31 Jul 2025

Viewed by 2708

Abstract

Mitochondria, pivotal organelles in cellular metabolism and energy production, have emerged as critical players in the pathogenesis of cancer. This review outlines the progress in mitochondrial profiling through mass spectrometry-based metabolomics and its applications in cancer research. We provide unprecedented insights into the [...] Read more.

Mitochondria, pivotal organelles in cellular metabolism and energy production, have emerged as critical players in the pathogenesis of cancer. This review outlines the progress in mitochondrial profiling through mass spectrometry-based metabolomics and its applications in cancer research. We provide unprecedented insights into the mitochondrial metabolic rewiring that fuels tumorigenesis, metastasis, and therapeutic resistance. The purpose of this review is to provide a comprehensive guide for the implementation of mitochondrial metabolomics, integrating advanced methodologies—including isolation, detection, and data integration—with insights into cancer-specific metabolic rewiring. We first summarize current methodologies for mitochondrial sample collection and pretreatment. Furthermore, we then discuss the recent advancements in mass spectrometry-based methodologies that facilitate the detailed profiling of mitochondrial metabolites, unveiling significant metabolic reprogramming associated with tumorigenesis. We emphasize how recent technological advancements have addressed longstanding challenges in the field and explore the role of mitochondrial metabolism-driven cancer development and progression for novel drug discovery and translational research applications in cancer. Collectively, this review delineates emerging opportunities for therapeutic discovery and aims to establish a foundation for future investigations into the therapeutic modulation of mitochondrial pathways in cancer, thereby paving the way for innovative diagnostic and therapeutic approaches targeting mitochondrial pathways. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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15 pages, 2681 KB  

Open AccessArticle

Metabolomic Profiling and Bioanalysis of Chronic Myeloid Leukemia: Identifying Biomarkers for Treatment Response and Disease Monitoring

by Selim Sayın, Murat Yıldırım, Batuhan Erdoğdu, Ozan Kaplan, Emine Koç, Tuba Bulduk, Melda Cömert, Mustafa Güney, Mustafa Çelebier and Meltem Aylı

Metabolites 2025, 15(6), 376; https://doi.org/10.3390/metabo15060376 - 6 Jun 2025

Cited by 4 | Viewed by 1478

Abstract

Background: Including Chronic Myeloid Leukemia (CML) patients with deep molecular responses (MR4.5) and those with suboptimal responses provides valuable insights into treatment-associated metabolic changes. This study aimed to characterize the metabolomic alterations associated with CML and identify potential biomarkers for treatment response, particularly [...] Read more.

Background: Including Chronic Myeloid Leukemia (CML) patients with deep molecular responses (MR4.5) and those with suboptimal responses provides valuable insights into treatment-associated metabolic changes. This study aimed to characterize the metabolomic alterations associated with CML and identify potential biomarkers for treatment response, particularly in patients achieving a deeper molecular response versus those with poorer responses. Methods: Plasma samples were collected from 51 chronic-phase CML patients and 24 healthy controls. CML patients were classified into two groups based on molecular responses: T1 (BCR-ABL1 IS ≤ 0.0032%) and T2 (BCR-ABL1 IS > 0.0032%, <1%). Metabolomic profiling was conducted using quadrupole time-of-flight liquid chromatography/mass spectrometry. The data analysis involved a partial least squares discriminant analysis, variable importance in projection (VIP) scores, and a pathway enrichment analysis. Significant metabolites were identified. Results: The PLS-DA revealed distinct metabolomic profiles between CML patients and healthy controls as well as between the T1 and T2 groups. Key differentiating metabolites with VIP scores > 1.5 included glutamate, hypoxanthine, and D-galactonic acid. In the T2 group, significant increases in malate and 5-aminoimidazole-4-carboxamide ribonucleotide were observed, reflecting disruptions in purine metabolism, the tricarboxylic acid cycle, and amino acid metabolism. The pathway enrichment analysis highlighted significant alterations in CML energy metabolism, nucleotide synthesis, and amino acid biosynthesis. Conclusions: CML patients exhibit pronounced metabolic changes, particularly in energy and nucleotide metabolism, which are linked to treatment response. These findings provide novel insights into CML biology and suggest potential biomarkers for monitoring treatment efficacy and predicting outcomes and therapeutic targets for improving treatment outcomes and overcoming tyrosine kinase inhibitor resistance. Full article

(This article belongs to the Topic Overview of Cancer Metabolism)

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