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However, it does not fully capture the immune\u2013metabolic heterogeneity underlying tumor\u2013microenvironment interactions within each subtype. Here, we integrate a validated immune\u2013metabolic gene signature as a functional layer to refine CMS classification and systematically characterize diversity across CMS1-4 tumors. Using transcriptomic data from 2918 CRC samples across three independent cohorts (GSE1, TCGA, and GSE2), we show that CMSs display robust yet distinct immune\u2013metabolic distributions across datasets. CMS4 tumors exhibit glycolytic, stromal-dependent, and immunosuppressive profiles, whereas CMS2 and CMS3 are enriched in oxidative and metabolically flexible states. Importantly, CMS1 tumors segregate into two major immune\u2013metabolic profiles, revealing marked heterogeneity within this immune-activated subtype. These patterns are preserved in metastatic samples, supporting their stability across disease stages. Overall, integrating immune\u2013metabolic profiling into CMSs reveals previously unrecognized functional heterogeneity and provides a refined framework to interpret tumor\u2013microenvironment states. This approach facilitates the identification of context-specific metabolic vulnerabilities with potential clinical relevance.<\/jats:p>","DOI":"10.3390\/biology15141128","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T16:30:37Z","timestamp":1783701037000},"page":"1128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune\u2013Metabolic Profiling Reveals Functional Heterogeneity Within Colorectal Cancer Consensus Molecular Subtypes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8135-7057","authenticated-orcid":false,"given":"Sergio","family":"Madurga","sequence":"first","affiliation":[{"name":"Department of Material Science and Physical Chemistry and Research Institute of Theoretical and Computational Chemistry of University of Barcelona (IQTCUB), Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"L\u00f3pez-Blanco","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carles","family":"Foguet","sequence":"additional","affiliation":[{"name":"British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB2 0SR, UK"},{"name":"Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge CB2 0SR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lahoz","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Gastrointestinal and Pancreatic Oncology Group, Institut D\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1801-1181","authenticated-orcid":false,"given":"Helena","family":"Oliveres","sequence":"additional","affiliation":[{"name":"Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Medical Oncology Department, Hospital Cl\u00ednic of Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinaldo","family":"Moreno","sequence":"additional","affiliation":[{"name":"Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Medical Oncology Department, Hospital Cl\u00ednic of Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Gorria","sequence":"additional","affiliation":[{"name":"Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Medical Oncology Department, Hospital Cl\u00ednic of Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1852-4975","authenticated-orcid":false,"given":"Leire","family":"Pedrosa","sequence":"additional","affiliation":[{"name":"Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Medical Oncology Department, Hospital Cl\u00ednic of Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0693-2207","authenticated-orcid":false,"given":"Silvia","family":"Marin","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Rojas","sequence":"additional","affiliation":[{"name":"Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, Medical Oncology Department, Hospital 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Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2062-4633","authenticated-orcid":false,"given":"Marta","family":"Cascante","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain"},{"name":"Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Biomedicine of Universitat de Barcelona (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal 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