ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1564213
This article is part of the Research TopicExploring key pathways in the progression of gastrointestinal diseases based on metabolic reprogramming and developing drugs targeting metabolismView all 3 articles
Sphingosine-1-phosphate stimulates colorectal cancer tumor microenvironment angiogenesis and induces macrophage polarization via macrophage migration inhibitory factor
Provisionally accepted- 1Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- 2Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
- 3Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- 4School of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia Autonomous Region, China
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Background: Colorectal cancer (CRC) is the most common gastrointestinal malignancy with extensive reprogramming of sphingolipid metabolism. However, the role and mechanisms of sphingosine-1-phosphate (S1P), a key bioactive molecule in sphingolipid metabolism, remain insufficiently characterized. Therefore, this study integrated multi-omics data to elucidate the characteristics and functions of S1P within the tumor microenvironment (TME) and investigated its role in angiogenesis through in vitro experiments.Methods: We used bulk RNA sequencing data sets (RNA-seq) to study the prognostic value and clinicopathological characteristics of the increased synthesis of S1P. In order to elucidate the contribution of S1P to the complexity of the tumor microenvironment, we employed intercellular communication analysis and functional enrichment analysis at the single-cell transcriptome (scRNA-seq) level. The expression of Sphingosine kinase 1 (SPHK1) in human tissues was verified by immunohistochemical staining (IHC). Then, we inhibited the synthesis of S1P by suppressing SPHK1 at the cellular level to explore the changes in the pro-angiogenic function of tumor cells and M2-like macrophages, as well as the direction of macrophage polarization.Results: S1P activity is elevated in the TME of CRC, and the increased synthesis of S1P suggests poor prognosis and early metastasis. intercellular communication analysis indicates that high S1P epithelial cells can promote angiogenesis and influence the polarization of tumor-associated macrophages (TAMs) through the macrophage migration inhibitory factor (MIF) pathway. TAMs were grouped according to gene expression patterns, in which, PCLAF+ cluster TAMs showed significantly high S1P activity, contributing to tumor growth and angiogenesis. IHC demonstrated elevated levels of SPHK1 protein expression in CRC tumor tissues. Inhibition of the synthesis of S1P in tumor cells and macrophages suppressed macrophage M2 polarization levels and reversed the pro-angiogenic phenotype by inhibiting VEGFA protein expression. Spatial transcriptomics revealed a correlation between the distribution of SPHK1 and M2-like macrophage.Conclusions: By integrating multi-omics data and further cellular experiments, we propose that inhibition of S1P may play an important role in inhibiting angiogenesis and reversing M2-type macrophage polarization, demonstrating its anti-tumor efficacy in CRC.
Keywords: Sphingosine-1-phosphate, tumor-associated macrophages polarization, Angiogenesis, colorectal cancer, ScRNA-seq
Received: 21 Jan 2025; Accepted: 27 May 2025.
Copyright: © 2025 Wu, Feng, Xuan, Guo, Wu, Bai, Lan, Chen and Ren. 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: Juan Ren, Department of Radiotherapy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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