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Increasing evidence has demonstrated that alterations in lipid synthesis, uptake, transport, and oxidation not only sustain tumor bioenergetics but also actively remodel the tumor immune microenvironment. Key lipid metabolic regulators\u2014including FASN, SREBP signaling, CD36-mediated lipid uptake, cholesterol metabolism, and fatty acid oxidation\u2014coordinate oncogenic signaling and promote immunosuppressive states characterized by T-cell exhaustion, macrophage polarization, and ferroptosis resistance, on the basis largely of correlative and preclinical evidence. Recent advances in multiomics technologies, including single-cell and spatial transcriptomics, metabolomics, and lipidomics, have enabled high-resolution mapping of lipid-dependent immune niches within metastatic CRC (mCRC) lesions. These approaches reveal lipid metabolism as a central organizer of tumor\u2013immune interactions and identify previously unrecognized metabolic vulnerabilities. In this review, we integrate current knowledge on lipid metabolic reprogramming in CRC with emerging multiomics insights, highlighting the mechanisms linking lipid metabolism, ferroptosis, gut microbiota interactions, and immune remodeling. We further discuss therapeutic strategies targeting lipid metabolic pathways and their potential synergy with immunotherapy. Collectively, the results of this work suggest that understanding lipid metabolism is a unifying framework for understanding mCRC biology and developing metabolism-guided therapeutic interventions.<\/jats:p>","DOI":"10.1186\/s12944-026-02956-9","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T07:58:55Z","timestamp":1777535935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Lipid metabolism as a central driver of immune remodeling and therapeutic vulnerability in metastatic colorectal cancer"],"prefix":"10.1186","volume":"25","author":[{"given":"Yuru","family":"Shang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runlin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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