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RESEARCH Open AccessJournal of Experimental & Clinical Cancer ResearchHellkamp et al. Journal of Experimental & Clinical Cancer Research (2026) 45:143 https://doi.org/10.1186/s13046-026-03755-xTargeting metabolic dependencies to reverse chemoradiotherapy resistance in colorectal cancerMaximilian Hellkamp 1† , Simon Gertken 1† , Jonas Buchloh 1 , Julius-Leonard Hellwig 1 , Lukas Ben Kowitzke 1 , Ningjun Duan 1 , Ilaria Gaspardo 1,2 , Stefan Küf f er 3 , Michael Linnebacher 4 , Philipp Ströbel 3,5 , Matthias Wirth 1,6 , Volker Ellenrieder 2,5,7 , Stefan Rieken 5,8 , Jochen Gaedcke 1,9 , Michael Ghadimi 1,5 , Jürgen Wienands 10 , Günter Schneider 1,2,5,11† , Melanie Spitzner 1*† and Marian Grade 1,2,5*†† Maximilian Hellkamp and Simon Gertken contributed equally to this work.† Günter Schneider, Melanie Spitzner and Marian Grade contributed equally to this work.*Correspondence:Melanie Spitznermelanie.spitzner@med.uni-goettingen.deMarian Grademarian.grade@med.uni-goettingen.deFull list of author information is available at the end of the article© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativ ecommon s.or g/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( h t t p : / / c r e a t i v e c o m m o n s . o r g / p u b l i c d o m a i n / z e r o / 1 . 0 / ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.AbstractNeoadjuvant chemoradiotherapy (CRT) constitutes a standard treatment for locally advanced rectal cancer (RC), frequently followed by radical surgical resection. Yet, therapeutic responses vary widely, and intrinsic radioresistance remains a major barrier to cure. To uncover actionable determinants of CRT response, we established a panel of patient-derived colorectal cancer cell lines (PDCLs) followed by integrated phenotypic and functional characterization. We identif i ed metabolic reprogramming as a hallmark of radioresistance and, through orthogonal validation experiments, conf i rmed elevated glycolytic and mitochondrial ATP production in (chemo)irradiation-resistant PDCLs. The causative relationship of this association and its potential for therapeutic intervention was shown by subsequent drug screening, showing resistance to most of the applied drugs and revealing a critical dependency on the monocarboxylate transporter (MCT1) and the glucose transporter 1 (GLUT1). Metabolism-targeting compounds re-sensitized resistant PDCLs to irradiation; especially inhibition of GLUT1 exhibits a robust radiosensitizing activity across models. Concordantly, GLUT1 expression correlated with poor response to neoadjuvant CRT in our own RC patient cohort and various publicly available patient datasets. Collectively, our study def i nes metabolic dependency as a key driver of CRT resistance in RC, and reveals glycolysis- and lactate-transport-associated pathway activities as targetable vulnerabilities. These fi ndings provide a mechanistic basis for patient stratif i cation and support the development of metabolism-directed strategies to overcome (chemo)radioresistance in RC.