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Review Open Access

Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review)

  • Authors:
    • Yun-Ta Chuang
    • I-Hui Wu
    • Cheng-Fan Lee
    • Hsinyu Lee
  • View Affiliations / Copyright

    Affiliations: School of Medicine, University of Lancashire, Preston, Lancashire PR1 2HE, UK, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA, Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Life Science, National Taiwan University, Taipei 10617, Taiwan, R.O.C.
    Copyright: © Chuang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 80
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    Published online on: May 4, 2026
       https://doi.org/10.3892/br.2026.2153
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Abstract

Sphingosine‑1‑phosphate (S1P) and its five G protein‑coupled receptors (S1PR1‑S1PR5) regulate a broad range of processes that shape cancer progression, including proliferation, survival, angiogenesis, immune evasion and metastatic dissemination. Under physiological conditions, this signaling axis contributes to vascular integrity, immune cell trafficking and tissue homeostasis. In cancer, however, its output is not solely determined by ligand abundances. Rather, tumors reprogram the S1P‑S1PR axis at a number of levels, coupling altered S1P production with receptor‑specific changes in expression, localization and the signaling state to generate context‑dependent malignant phenotypes. The present review provided a receptor‑resolved synthesis of S1PR functions in cancer and examined the mechanisms that underlie pathway dysregulation, including transcriptional activation, epigenetic remodeling, microRNA loss, post‑translational modifications and altered receptor trafficking and compartmentalization. It further discussed how metabolic amplification of S1P availability cooperates with receptor‑level rewiring to sustain tumor progression, microenvironmental remodeling and therapeutic resistance. This framework positions the S1P‑S1PR axis as a dynamically reprogrammed signaling network and highlights therapeutic strategies that concurrently target S1P production and receptor‑mediated signaling as promising avenues for more‑precise, biomarker‑informed cancer treatment.
View Figures

Figure 1

Overview of the S1P-S1PR signaling
axis in cancer. Sphingomyelin is hydrolyzed to ceramide by SMase
and ceramide is subsequently converted to sphingosine by
ceramidase. Sphingosine is phosphorylated by SphK1 to generate S1P,
which is exported by transporters such as SPNS2. Extracellular S1P
binds S1PR isoforms and activates downstream Gi-, Gq- and
G12/13-dependent signaling pathways, including Rho, AC, Ras, PI3K,
STAT3 and PLC, thereby promoting tumor-associated processes. S1P,
sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate receptor;
SMase, sphingomyelinase; SphK1, sphingosine kinase 1; SPNS2,
spinster homolog 2; Gi, G protein alpha i; Gq, G protein alpha q;
G12/13, G protein alpha 12/13; AC, adenylyl cyclase; PI3K,
phosphatidylinositol 3-kinase; STAT3, signal transducer and
activator of transcription 3; PLC, phospholipase C.

Figure 2

Multilevel reprogramming of the
S1P-S1PR axis in cancer. Within tumor cells, the S1P-S1PR axis is
reprogrammed at multiple levels. Transcriptional rewiring,
epigenetic remodeling and loss of miRNA-mediated repression reshape
S1PR isoform expression and receptor abundance. In parallel,
increased SphK1 activity and reduced S1P lyase activity create a
ligand-rich state that promotes intracellular S1P accumulation and
S1P signaling in the tumor microenvironment. Together, these
changes alter receptor abundance, compartmentalization and
signaling competence at the plasma membrane, converting a
homeostatic pathway into a context-dependent driver of malignancy.
S1P, sphingosine-1-phosphate; S1PR, sphingosine-1-phosphate
receptor; SphK1, sphingosine kinase 1; miRNA, microRNA.
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Copy and paste a formatted citation
Spandidos Publications style
Chuang Y, Wu I, Lee C and Lee H: Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review). Biomed Rep 25: 80, 2026.
APA
Chuang, Y., Wu, I., Lee, C., & Lee, H. (2026). Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review). Biomedical Reports, 25, 80. https://doi.org/10.3892/br.2026.2153
MLA
Chuang, Y., Wu, I., Lee, C., Lee, H."Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review)". Biomedical Reports 25.1 (2026): 80.
Chicago
Chuang, Y., Wu, I., Lee, C., Lee, H."Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review)". Biomedical Reports 25, no. 1 (2026): 80. https://doi.org/10.3892/br.2026.2153
Copy and paste a formatted citation
x
Spandidos Publications style
Chuang Y, Wu I, Lee C and Lee H: Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review). Biomed Rep 25: 80, 2026.
APA
Chuang, Y., Wu, I., Lee, C., & Lee, H. (2026). Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review). Biomedical Reports, 25, 80. https://doi.org/10.3892/br.2026.2153
MLA
Chuang, Y., Wu, I., Lee, C., Lee, H."Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review)". Biomedical Reports 25.1 (2026): 80.
Chicago
Chuang, Y., Wu, I., Lee, C., Lee, H."Decoding the S1P‑S1PR axis in cancer: Mechanisms, pathways and therapeutic horizons (Review)". Biomedical Reports 25, no. 1 (2026): 80. https://doi.org/10.3892/br.2026.2153
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