(Matesanz-Sanchez and Classen et al., Cell Communication & Signalling 2026)
Metabolic processes are increasingly identified as determinants of tumour radiation resistance and as potential therapeutic targets. Cancer cells preferentially rely on glutamine, polyamine, lipid, and glucose metabolism. Among these glycose supply is most important, and is primarily provided by aerobic glycolysis (Warburg effect ) [1].
This shift not only generates adenosine triphosphate but also fuels biosynthesis, supports angiogenesis, and turns the tumour microenvironment into an acidic, immunosuppressive niche that promotes invasion and metastasis [2,3].
At the core of this metabolic network lies glycolysis, which is initiated by glucose transporters (GLUTs 1–3) and culminates in the production of pyruvate − a critical hub metabolite for amino acid and lipid synthesis [4]. This network is closely linked to the survival of patients with breast cancer and immune evasion through the upregulation of the expression of programmed cell death ligand 1 [5]. Pyruvate kinase (PK), in one of its four isoforms, PKL, PKR, and glycolysis-associated pyruvate kinase M (PKM1 and PKM2) is the terminal key enzyme in glycolysis. PKM2 is overexpressed in various cancer types. However, its role in therapy resistance is controversial, and this underscores the need for a deep mechanistic understanding [1].
To address this, we applied non-targeted metabolomics to dissect the metabolic response of cells of triple-negative breast cancer (TNBC) to irradiation. Integrating metabolite profiling with functional genomics, we identified a network of 44 metabolite-associated genes and, through RNA interference screening, uncovered nine candidates with radiosensitising potential [6]. Among these was PKM, whose high expression in the METABRIC TNBC cohort was associated with a poorer overall survival rate of patients.
Pharmacological PKM inhibition led to radiosensitisation in TNBC cell models, which was attributed to the selective disruption of S-phase processes. This led to both reduced rates of DNA synthesis and increased replication stress, as evidenced by increased DNA damage at active replication forks, and resulted in prolonged cell-cycle arrest after irradiation.
It has been observed that without irradiation, DNA replication is directly impaired if intermediates of glycolysis and the tricarboxylic acid cycle accumulate [7]. It has also been found that the DNA damage response is modulated indirectly by the availability of nucleotides, a shift in the redox balance, and altered activity of DNA repair proteins [8]. In fact, in our cell models, PKM inhibition combined with irradiation led to an increase in levels of pan-nuclear γH2AX and a general slowing of DNA replication—both hallmarks of replicative stress [9]—as well as to an accumulation of cells in the G2 phase.
PKM2 is a known substrate of ataxia-telangiectasia mutated and promotes homologous recombination by phosphorylating the C-terminal binding protein-interacting protein [10]; however, our data suggest that this signalling pathway is insufficient to repair the damage that occurs under PKM inhibition. In particular, the observed increase in co-localisation of RAD51/γH2AX probably reflects ongoing recruitment of proteins involved in homologous recombination to stalled or collapsed replication forks, rather than efficient completion of repair. Taken together, these data support a model in which the metabolic disturbances that are induced by PKM inhibition could exacerbate replication-related DNA damage after irradiation, leading to prolonged G2 arrest and the accumulation of unresolved genomic lesions.
In addition, we have identified a group of genes that were associated with PKM-induced changes in the metabolome, correlated with PKM expression, and linked to the effects of PKM on cell survival and the radiation response (i.e., α-enolase, glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate isomerase; “Cluster 2”). These glycolytic genes have previously been linked individually to metastasis, adaptation to hypoxia, tumour aggressiveness, and cellular stress response [11-13]. Thus, they all contribute to the reprogramming of cancer metabolism and are associated with a poor prognosis. Therefore, they may contribute to treatment resistance. This is consistent with our observation that patients with high expression of Cluster 2 show a poorer response to radiation therapy than do those with low expression.
Going beyond studies that link glycolysis-related gene signatures to therapeutic response in TNBC [14], we have demonstrated for the first time that a glycolysis-related gene cluster has prognostic value for the outcomes of radiation therapy. Notably, this prognostic value extends beyond TNBC to patients with head-and-neck squamous cell carcinoma, and this suggests that this metabolic signature could serve as a potential biomarker for various tumour types.
Our study demonstrates that non-targeted metabolomics is a promising tool for the identification of new therapeutic targets. By investigating the metabolomic changes that are induced in irradiated TNBC cells, we have identified possible clinically relevant targets whose inhibition could improve the response to radiation therapy in TNBC patients. We demonstrate in this study that PKM and its associated genes may offer therapeutic vulnerabilities. Work is required to clarify the therapeutic relevance of PKM and its associated enzymes. Our research clearly underscores the utility of metabolomics to improve cancer treatment.
Kerstin Borgmann
Kerstin Borgmann1, Rocio Matesanz-Sánchez2, Sandra Classen1, and Nils Cordes2-5
1Department of Radiotherapy & Radiation Oncology, Hubertus Wald Tumour Centre- University Cancer Centre Hamburg, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
2OncoRay—National Centre for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
3Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
4German Cancer Consortium (DKTK), Partner Site Dresden: German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany
5Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
Correspondence to borgmann@uke.de
References
1. Dong S and Li T. Metabolic reprogramming in cancer: signaling pathways and therapeutic targets. Mol Cancer. 2026 Feb 3;25(1):60. doi: 10.1186/s12943-026-02582-0.
2. Liu S, et al. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer. Mol Cancer. 2024;23(1):261.
3. Kooshan Z, et al. Glycolysis, the sweet appetite of the tumor microenvironment. Cancer Lett. 2024;600:217156.
4. Zhao L, et al. UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. J Exp Clin Cancer Res. 2022;41(1):330.
5. Lin J, et al. Glycolytic enzyme HK2 promotes PD-L1 expression and breast cancer cell immune evasion. Front Immunol. 2023;14:1189953.
6. Matesanz-Sánchez R, et al. Cell Commun Signal. 2026 Mar 12. doi: 10.1186/s12964-026-02803-5. Online ahead of print.
7. Lunt SY, et al. Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol Cell. 2015;57(1):95–107.
8. Bailleul J, et al. M2 isoform of pyruvate kinase rewires glucose metabolism during radiation therapy to promote an antioxidant response and glioblastoma radioresistance. Neuro Oncol. 2023;25(11):1989–2000.
9. Saxena S, and Zou L. Hallmarks of DNA replication stress. Mol Cell. 2022;82(12):2298–314.
10. Sizemore ST, et al. Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair. Cell Res. 2018;28(11):1090–102.
11. Huang CK, et al. ENO1 and Cancer. Mol Ther Oncolytics. 2022;24(March):288–98.
12. Wang J, et al. GAPDH: A common housekeeping gene with an oncogenic role in pan-cancer. Comput Struct Biotechnol J. 2023;21(July):4056–69.
13. de Padua MC, et al. Disrupting glucose-6-phosphate isomerase fully suppresses the “Warburg effect” and activates OXPHOS with minimal impact on tumor growth except in hypoxia. Oncotarget. 2017;8(50):87623–37.
14. Zheng J, et al. Identification and validation of a novel glycolysis- related gene signature for predicting the prognosis and therapeutic response in triple-negative breast cancer. Adv Ther. 2023;40(1):310–30.