{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T01:52:18Z","timestamp":1781488338816,"version":"3.54.1"},"reference-count":443,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality, with substantial heterogeneity that is not fully explained by genetic alterations alone. Emerging evidence positions metabolic reprogramming as a central driver of tumor behavior, integrating glycolysis, mitochondrial function, lipid and amino acid metabolism, and autophagy into coordinated networks that extend beyond cancer cells to the tumor microenvironment. Tumor\u2013immune metabolic competition and metabolite-mediated signaling shape immune responses, often promoting immunosuppression and resistance to immunotherapy, particularly in microsatellite-stable (MSS) CRC. Systemic factors, including obesity, insulin resistance, and the diet\u2013microbiota axis, further modulate tumor metabolism and immune function, reinforcing disease progression. Metabolic biomarkers reflecting these multi-level interactions, spanning tumor-intrinsic pathways, immune contexture, and host metabolism, offer promising opportunities for improved patient stratification and therapeutic targeting, although clinical validation remains limited. Current treatments, including chemotherapy, targeted agents, and immune checkpoint inhibitors, are effective in selected subgroups but are constrained by resistance mechanisms. In this review, we propose an integrative immunometabolic framework in which tumor, immune, and systemic metabolic processes co-evolve, defining CRC progression and treatment response. Targeting this interconnected network through combinatorial and metabolism-oriented strategies may enable precision therapies, particularly for immunotherapy-resistant MSS CRC.<\/jats:p>","DOI":"10.3390\/cells15121074","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:44:58Z","timestamp":1781484298000},"page":"1074","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Determinants of Colorectal Cancer: An Integrative Immunometabolic Framework Linking Biomarkers, Therapy, and the Diet\u2013Microbiota Axis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-0805","authenticated-orcid":false,"given":"Gianluca","family":"Aguiari","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Rehabilitation, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9280-6017","authenticated-orcid":false,"given":"Nicoletta","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Franzese","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1470-2045(24)00600-4","article-title":"Colorectal Cancer Incidence Trends in Younger versus Older Adults: An Analysis of Population-Based Cancer Registry Data","volume":"26","author":"Sung","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zheng, S., Schrijvers, J.J.A., Greuter, M.J.W., Kats-Ugurlu, G., Lu, W., and de Bock, G.H. 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