ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1649788
This article is part of the Research TopicMolecular Pathways and Signaling Molecules in Cancer Therapy: Advances and InnovationsView all 10 articles
Integrative multi-omics identification and functional validation of potential targets linking metabolism-immune-colorectal cancer causal pathway
Provisionally accepted
- 1Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, China
- 2The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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Background: Colorectal cancer (CRC) remains a major global health burden, highlighting the need for novel molecular targets for therapy and prognosis. This study integrates multi-omics data with functional assays to explore metabolite-mediated mechanisms in CRC risk.Methods: We performed genetic causal inference and colocalization analyses using genome-wide association data to assess causality between 233 metabolites and CRC. A total of 731 immune traits were investigated as potential mediators. Metaboliteassociated CpG sites were identified via epigenome-wide association studies (EWAS), and their methylation QTLs (mQTLs) were linked to target genes through interaction eQTL analysis via FUMAGWAS. Expression, prognosis, immune infiltration, and regulatory associations of target genes were analyzed using TCGA datasets. Functional assays were conducted in NCM460 and CRC cell lines (HCT116, SW480, CACO2).Results: A higher omega-3 fatty acid ratio (FAw3byFA, OR = 1.22, P = 2.51×10⁻⁷) was associated with increased CRC risk, with partial mediation (10%) via Effector Memory CD4⁺ T cells. Colocalization (PP.H4 ≈ 0.97) suggested shared genetic loci.Genetically predicted Omegaomega-3-associated CpG sites, cg05181941, cg06817802, and cg22456785, were causally linked to CRC risk. These sites-derived 428 mQTLs interact with eQTL genes, highlighting SLC6A19 as a potential target, expressed in CD4⁺ T cells and colon tissue. SLC6A19 was downregulated in TCGA-COAD, -READ, and -COADREAD and confirmed by immunoblotting, correlating with poor survival and CD4⁺ T cell infiltration. CCK-8, wound healing, and Transwell assays showed that 3 SLC6A19 overexpression suppressed CRC cell proliferation, migration, and invasion.Conclusions: Omega-3-related methylation-intersecting SLC6A19 potentially mediates omega-3-CD4⁺ T cells-driven CRC risk, suggesting a candidate inhibitory target.
Keywords: colorectal cancer (CRC), multiomics, omega-3 polyunsaturated fatty acids, CD4+ T cell, SLC6A19
Received: 19 Jun 2025; Accepted: 20 Aug 2025.
Copyright: © 2025 Xu, Zheng, Chen and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiaojun Xie, Department of General Surgery, First Affiliated Hospital of Shantou University Medical College, Shantou, China
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