Cancer metabolism has become one of the most studied aspects of the "hallmarks of cancer." It refers to alterations in how tumor cells process nutrients to fuel their rapid proliferation and spread. These dramatic dysregulations include elevated glucose uptake even in the presence of oxygen (the Warburg effect), dependence on glutamine, and the production of waste products such as lactate, which further support tumor growth and metastasis. Genetic mutations accumulating during cancer progression in metabolic enzymes and cancer-promoting signaling pathways directly affect metabolic changes in cancer cells as well as in the tumor microenvironment [1,2].

A growing number of scientists are developing targeted therapies to exploit these metabolic differences to slow or halt cancer progression. Some therapies aim to block or alter the production of specific metabolites, while several drugs for other pathologies, such as diabetes, are of great interest due to their potential to slow tumor growth by altering systemic metabolic factors such as insulin and glucose levels in a "drug repositioning" strategy [3-7].

Cancer metabolism, involving altered lipid, iron, and amino acid pathways, regulates ferroptosis, an iron-dependent, lipid peroxidation-driven form of cell death. Cancer cells often resist this process, but targeting their specific metabolic vulnerabilities, such as glutathione depletion or iron overload, can trigger ferroptosis to kill tumor cells and overcome drug resistance [8].

Cancer cells can rewire their metabolism when one pathway is blocked, so it is becoming clear that combining metabolism inhibitors with traditional chemotherapy, radiotherapy, or immunotherapy may be an effective therapeutic strategy [8]. While some metabolism-targeting drugs have been successful (e.g., in Acute Lymphocytic Leukemia), targeting cancer metabolism is complex due to its similarity to normal cell processes [9]. Metabolic profiling of patients is helping to identify specific vulnerabilities, leading to more personalized metabolic therapies [10].

Understanding cancer metabolism at a deeper mechanistic level is also essential to improving immunotherapy, as immune cell metabolism changes during therapy administration, contributing to acquired resistance.

KEYWORDS: metabolomics; proteomics, genomics, mitochondrial metabolism, ferroptosis, oxidative stress, inflammation, innovative study models, new translational therapeutic approaches.

In this Collection of the Journal of Experimental & Clinical Cancer Research, we would like to promote studies that further dissect the molecular mechanisms through which cancer cells reprogram their own metabolism and that of cells in the tumor microenvironment, thus driving disease progression. Furthermore, studies that highlight potential metabolic vulnerabilities that could be targeted therapeutically will be of interest.

References

1. Finley LWS. What is cancer metabolism? Cell. 2023;186(8):1670-88. PubMed PMID: 36858045. PMCID: PMC10106389.eng
2. Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer. 2023;23(3):156. PubMed PMID: 36658431. PMCID: PMC11137663.eng
3. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10(9):671-84. PubMed PMID: 21878982.
4. Zou W, Han Z, Wang Z, Liu Q. Targeting glutamine metabolism as a potential target for cancer treatment. J Exp Clin Cancer Res. 2025;44(1):180. PubMed PMID: 40598593. PMCID: PMC12210561.
5. Formenti L, Abramo F, Dellavedova G, Dematteis V, Decio A, Grasselli C, et al. Impairment of oxidative metabolism compromises Rad51 recruitment and potentiates PARP inhibitor effectiveness in ovarian cancer. J Exp Clin Cancer Res. 2026;45(1):45. PubMed PMID: 41530766. PMCID: PMC12888472.
6. Chen T, Xu ZG, Luo J, Manne RK, Wang Z, Hsu CC, et al. NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance. Cell Metab. 2023;35(10):1782-98.e8. PubMed PMID: 37586363. PMCID: PMC10726430.
7. Pillai U J, Ray A, Maan M, Dutta M. Repurposing drugs targeting metabolic diseases for cancer therapeutics. Drug Discov Today. 2023;28(9):103684. PubMed PMID: 37379903.
8. Wu Y, Li H, Yue K, Jing C, Duan Y. Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects. Mol Cancer. 2025;24(1):303.
9. Punnasseril JMJ, Auwal A, Gopalan V, Lam AK, Islam F. Metabolic Reprogramming of Cancer Cells and Therapeutics Targeting Cancer Metabolism. Cancer Med. 2025;14(18):e71244. PubMed PMID: 40956032. PMCID: PMC12439291.
10. da Silva-Diz V, Herranz D. Unleashing the Full Potential of Metabolic Interventions in T-ALL. Blood Cancer Discov. 2025;6(3):163-7. PubMed PMID: 40111138. PMCID: PMC12050939.
11. Benjamin DI, Cravatt BF, Nomura DK. Global profiling strategies for mapping dysregulated metabolic pathways in cancer. Cell Metab. 2012;16(5):565-77. PubMed PMID: 23063552. PMCID: PMC3539740.