Sphingosine 1-phosphate derived from tumor-educated hepatic stellate cells combining with S1PR4 promotes tumor associated macrophages differentiation through FAO modulation.

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.