Aims and Objectives: Sphingosine-1-phosphate (S1P) is a membrane derived bioactive phospholipid exerting a multitude of effects on respiratory cell physiology and pathology through five S1P receptors (S1PR1-5), although its exact mechanism is still elusive and contradictory. In our previous studies, we found that S1P induced proliferation of epithelial lung cancer cells through a S1PR3/SPHK II (S1P receptor 3/Sphingosine Kinase II)-dependent intracellular/intranuclear signalling. In this study we aimed to shed light on the role of S1P, whose levels are elevated in lung cancer patientsâ?? plasma, as a modulator of tumor microenvironment, focusing on its effect on circulating cells. Methods : We used peripheral blood mononuclear cells (PBMCs) isolated by healthy volunteers and lung cancer patients. Cells were stimulated with S1P 10nM and the release of pro-inflammatory cytokines was evaluated after 8 hours from the treatment. Results: We found that lung cancer-derived PBMCs expressed higher levels of S1PR3 and active ceramidase, compared to healthy cells. Moreover, the administration of S1P induced the release of TNFÎ±, IL-6 and IL-8 from lung cancer- but not from healthy-derived PBMCs in a ceramidase and SPHKs-dependent manner. Interesting, only IL-6 release was S1PR3 dependent. Conclusions: Our data suggest that S1P regulate the pro-inflammatory signalling in pathological conditions, but not in physiological conditions where S1PR3 is poor expressed and ceramidase enzyme is inactive, implying a protective role of S1P in physiological conditions and highlighting S1P as one of the crucial mediators for lung carcinogenesis-associated inflammatory processes.