Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation
Abstract The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathwa...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-02588-6 |
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| author | Rui Feng Zilin Cui Long Yang Zirong Liu |
| author_facet | Rui Feng Zilin Cui Long Yang Zirong Liu |
| author_sort | Rui Feng |
| collection | DOAJ |
| description | Abstract The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathways. Sphingosine 1-phosphate (S1P) is involved in immune regulation as a lipid metabolite. The role of S1P in the differentiation and metabolic regulation of tumor-associated macrophages is unknown. Meanwhile, the source of S1P in TME is not very clear. Our research found that hepatic stellate cells co-cultured with tumor cells could prompt macrophages to the M2 phenotype of TAM differentiation. It was further discovered that S1P activated peroxisome proliferator-activated receptor α (PPARα) by binding to S1P receptor 4 (S1PR4) of macrophages, upregulating lipid metabolism and inducing the TAM differentiation. Ultimately, tumor cells activated nuclear factor erythroid 2-related factor 2 (Nrf2) in hepatic stellate cells (HSCs), enhancing sphingosine kinase 1 (SphK1) expression and elevating S1P production and secretion. This study has demonstrated a possible interaction pathway among tumor cells, HSCs and macrophages. It has revealed that tumor cells activate the Nrf2/SphK1 pathway in HSCs to secrete S1P, which subsequently bound S1PR4, triggered PPARα activation, and drove macrophage polarization toward pro-tumor M2-type TAMs. |
| format | Article |
| id | doaj-art-158a31f5c2dd498f97301b890054c19c |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-158a31f5c2dd498f97301b890054c19c2025-08-20T04:01:41ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-02588-6Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulationRui Feng0Zilin Cui1Long Yang2Zirong Liu3Department of Hepatobiliary Surgery, Tianjin First Central HospitalDepartment of Hepatobiliary Surgery, Tianjin First Central HospitalDepartment of Hepatobiliary Surgery, Tianjin First Central HospitalDepartment of Hepatobiliary Surgery, Tianjin First Central HospitalAbstract The tumor immune microenvironment (TIME) is significance to the occurrence and development of tumors. Macrophages, making great contributes to TIME, develop into tumor-associated macrophages (TAM) under the influence of the tumor microenvironment (TME), resulting in altered metabolic pathways. Sphingosine 1-phosphate (S1P) is involved in immune regulation as a lipid metabolite. The role of S1P in the differentiation and metabolic regulation of tumor-associated macrophages is unknown. Meanwhile, the source of S1P in TME is not very clear. Our research found that hepatic stellate cells co-cultured with tumor cells could prompt macrophages to the M2 phenotype of TAM differentiation. It was further discovered that S1P activated peroxisome proliferator-activated receptor α (PPARα) by binding to S1P receptor 4 (S1PR4) of macrophages, upregulating lipid metabolism and inducing the TAM differentiation. Ultimately, tumor cells activated nuclear factor erythroid 2-related factor 2 (Nrf2) in hepatic stellate cells (HSCs), enhancing sphingosine kinase 1 (SphK1) expression and elevating S1P production and secretion. This study has demonstrated a possible interaction pathway among tumor cells, HSCs and macrophages. It has revealed that tumor cells activate the Nrf2/SphK1 pathway in HSCs to secrete S1P, which subsequently bound S1PR4, triggered PPARα activation, and drove macrophage polarization toward pro-tumor M2-type TAMs.https://doi.org/10.1038/s41598-025-02588-6 |
| spellingShingle | Rui Feng Zilin Cui Long Yang Zirong Liu Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation Scientific Reports |
| title | Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation |
| title_full | Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation |
| title_fullStr | Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation |
| title_full_unstemmed | Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation |
| title_short | Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation |
| title_sort | sphingosine 1 phosphate derived from tumor educated hepatic stellate cells combining with s1pr4 promotes tumor associated macrophages differentiation through fao modulation |
| url | https://doi.org/10.1038/s41598-025-02588-6 |
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