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  • The Interplay of Intratumoral Microbiome and Lipid Metabolism in the Colorectal Cancer Microenvironment: From Molecular Mechanisms to Therapeutic Perspectives

  • Amir Hossein Shahrestani,1,*
    1. Student Research Committee, Jahrom University of Medical Sciences, Jahrom, Iran


  • Introduction: The discovery of a rich intratumoral microbiome has revolutionized our understanding of colorectal cancer (CRC). Emerging evidence indicates that tumor-resident bacteria critically influence CRC progression through metabolic reprogramming, particularly by modulating lipid metabolism within the tumor microenvironment (TME). This narrative synthesis aims to systematically review current evidence on how intratumoral bacteria reprogram lipid metabolism in CRC, elucidate the molecular mechanisms, and explore therapeutic implications.
  • Methods: A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science for articles published from January 2020 to August 2026. Search terms combined concepts of "intratumoral microbiome," "lipid metabolism," and "colorectal cancer." Inclusion criteria: original research (in vitro, in vivo, or clinical) and systematic reviews examining intratumoral bacteria–lipid metabolism interactions in CRC, published in English. Exclusion criteria: studies on gut microbiota without intratumoral focus, no lipid metabolism outcomes, conference abstracts, editorials, and duplicates. Quality and bias were assessed using SYRCLE's Risk of Bias Tool (animal studies), Newcastle-Ottawa Scale (observational human studies), and QUIN checklist (in vitro studies). A narrative (thematic) synthesis was performed due to study heterogeneity.
  • Results: Three distinct mechanistic axes were identified. First, chronic ATF6 activation in intestinal epithelial cells enriches long-chain fatty acids, selectively promoting expansion of tumor-associated Desulfovibrio fairfieldensis (Nature Metabolism, 2025). Second, Fusobacterium nucleatum activates NF-κB, upregulating miR-130a-3p, which suppresses AMPK and releases SREBF2, thereby enhancing cholesterol biosynthesis genes (FDPS, FDFT1, SQLE) (Cancer Letters, 2025); butyrate counteracts this pathway. Third, colibactin-producing E. coli establishes a glycerophospholipid-overloaded, immunosuppressive microenvironment facilitating chemoresistance (Gut Microbes, 2024). Integrative TCGA analysis of 420 COAD patients revealed FAM pathway activity significantly correlates with distinct microbial signatures and TME remodeling, impacting prognosis and immunotherapy response.
  • Conclusion: The intratumoral microbiome–lipid metabolism axis represents a critical driver of CRC pathogenesis. Host-driven lipid alterations shape microbial communities, while bacteria-driven lipid reprogramming directly promotes oncogenesis and immune evasion. Therapeutic opportunities include targeting FASN/SREBF2, modulating the microbiome with probiotics (e.g., butyrate) or phage therapy, and inhibiting lipid accumulation. Limitations include heterogeneity of study designs and predominance of preclinical data. Nonetheless, understanding this "unresolved trinity" paves the way for novel biomarkers and personalized therapeutic strategies in CRC precision medicine.
  • Keywords: Intratumoral microbiome, lipid metabolism, colorectal cancer, Fusobacterium nucleatum, ATF6

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