Here, by using our established obesity-lymphoma mouse models as well as the lymphoma cell lines and a monocyte cell line, we revealed the potential mechanism of S1P/SPHK1 signaling in contribution to obesity-lymphomagenesis, in particular, the S1P-YAP axis in lymphoma cells and the S1P-mediated polarization of macrophages in the tumor microenvironment. Here, SPHK1 is linked to obesity disorder.