Sphingosine kinase 1 (SPHK1) is upregulated in tumour cells to produce sphingosine-1-phosphate (S1P); this activates S1P receptor 1 (S1PR1), which leads to the activation of signal transducer and activator of transcription 3 (STAT3). Reciprocally, STAT3 enhances the transcription of its target genes, including S1PR1. S1P is also involved in the activation of nuclear factor-κB (NF-κB), which regulates the transcription of the pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin-6 (IL-6). TNF stimulates SPHK1 to further maintain NF-κB activation, and IL-6 induces STAT3 activation. In addition to upregulating SPHK1 in tumour cells, inflammation upregulates SPHK1 in inflammatory and/or myeloid cells in a manner similar to that in tumour cells. Communication among tumour cells, the host microenvironment and inflammatory cells via systemic S1P regulates metastasis. Targeting SPHK1 and S1PR1 — for example, with fingolimod — interferes with these amplification cascades and cancer progression. IL-6R, IL-6 receptor; TNFR, TNF receptor; TRAF2, TNF receptor-associated factor 2.