Fluxes and Functions of the Sphingolipid Cycle Within the Tumor Microenvironment

Sphingolipids are a bioactive family of lipids essential for maintaining the physical and chemical properties of membranes and acting as signaling messenger molecules. Recent studies have illuminated the cell biological roles that these lipids play in cancer contexts. These lipids are implicated across cancer types, playing roles in cell death, proliferative signaling, and therapeutic responses. Here, we review findings describing the roles of ceramide, sphingomyelin, glycosphingolipids, and sphingosine-1-phosphate in the cell-intrinsic mechanistic functions in malignancy and in the cross talk that occurs between diverse cell types within the tumor microenvironment. We describe how these diverse lipids operate in a sphingolipid cycle with numerous inputs and outputs spanning organelles and cells across the tumor microenvironment. We also discuss the contributions of this pathway to the metastatic cascade. Finally, we summarize previous therapeutic shortcomings and the current outlook of targeted therapeutic strategies, contextualizing our existing knowledge within their respective clinical applications.