S1PR1 and neoplasm: Other studies have reported that SPHK2/S1P can impact the proliferation and metastasis of various cancers [35, 36] and that the combination of S1P and S1PR1 can activate STAT3, with the latter, in return, positively regulating the transcription of S1PR1, which persistently activates STAT3, setting in motion a positive feedback cycle and altering the microenvironment and permeability of the BBB, so as to enhance tumor growth and BM metastasis [47–49] On the basis of these findings, we hypothesize that RPTOR might boost the SPHK2/S1P/STAT3 cascades and promote the BM (Fig. 6).