TNF and lung cancer: In particular, the activation of S1PR3 on lung cancer-derived PBMCs by the exogenous S1P enhances its own metabolism and fosters the release of TNF-α in a SPHK I-dependent manner (Figure 6, black arrows), and of IL-6 via SPHK I/II (Figure 6, red arrows); S1P-induced IL-6, but not TNF-α, is mTOR- and K-Ras-dependent (Figure 6, red arrows).