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Objective <p>Sphingosine-1-phosphate receptor 4 (S1PR4), a G protein-coupled receptor predominantly expressed in immune cells, plays crucial yet complex roles in cancer biology and pain signaling. The current study was designed to evaluate its diagnostic, prognostic, and immunomodulatory roles while further exploring the molecular mechanisms underlying its dual functions in both tumor progression and pain regulation.</p> Methods <p>Through integrated analysis of TCGA, GTEx, TISIDB, GEPIA and other multi-omics databases, we performed a comprehensive pan-cancer characterization of S1PR4. We systematically evaluated the differential expression of S1PR4 between tumor and normal tissues, investigated its correlation with pain-related inflammatory molecules, and validated its expression patterns across pan-cancer cohorts. The prognostic value of S1PR4 was determined through survival analysis, while its diagnostic efficacy was assessed using ROC curve analysis. Furthermore, we characterized its association with immune subtypes and examined its correlation with immune cell infiltration. Finally, the expression profile of S1PR4 within the tumor microenvironment was verified using single-cell RNA sequencing data. We also conducted further validation of its value in BRCA.</p> Results <p>We identified S1PR4 as a pivotal determinant of cancer pain, showing significant correlation with multiple algogenic molecules. Analysis across 24 cancer types revealed distinct dysregulation patterns, with significant diagnostic value (AUC &gt; 0.80) in SKCM, HNSC, and THYM. Survival analysis demonstrated its protective role in most cancers except GBM, UVM, and PRAD. S1PR4 expression was enriched in immunologically active subtypes (C2/C3) and correlated specifically with CD4 + T cells, B cells, and myeloid-derived suppressor cells. Single-cell sequencing results indicated that the expression of S1PR4 was elevated in tumor cells of specific cancer types, such as GBM. In BRCA, S1PR4 coordinated an immunoregulatory network containing novel prognostic determinants.</p> Conclusion <p>These findings establish S1PR4 as a multifaceted regulator of tumor immunity and cancer pain, providing a dual-targeting strategy for precision oncology.</p>

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S1PR4 connects cancer pain to pan-cancer mechanisms and reveals prognosis, immune infiltration and therapeutic potential

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • Peng Ke,
  • Chengjie Zheng,
  • Xiaodan Wu

摘要

Objective

Sphingosine-1-phosphate receptor 4 (S1PR4), a G protein-coupled receptor predominantly expressed in immune cells, plays crucial yet complex roles in cancer biology and pain signaling. The current study was designed to evaluate its diagnostic, prognostic, and immunomodulatory roles while further exploring the molecular mechanisms underlying its dual functions in both tumor progression and pain regulation.

Methods

Through integrated analysis of TCGA, GTEx, TISIDB, GEPIA and other multi-omics databases, we performed a comprehensive pan-cancer characterization of S1PR4. We systematically evaluated the differential expression of S1PR4 between tumor and normal tissues, investigated its correlation with pain-related inflammatory molecules, and validated its expression patterns across pan-cancer cohorts. The prognostic value of S1PR4 was determined through survival analysis, while its diagnostic efficacy was assessed using ROC curve analysis. Furthermore, we characterized its association with immune subtypes and examined its correlation with immune cell infiltration. Finally, the expression profile of S1PR4 within the tumor microenvironment was verified using single-cell RNA sequencing data. We also conducted further validation of its value in BRCA.

Results

We identified S1PR4 as a pivotal determinant of cancer pain, showing significant correlation with multiple algogenic molecules. Analysis across 24 cancer types revealed distinct dysregulation patterns, with significant diagnostic value (AUC > 0.80) in SKCM, HNSC, and THYM. Survival analysis demonstrated its protective role in most cancers except GBM, UVM, and PRAD. S1PR4 expression was enriched in immunologically active subtypes (C2/C3) and correlated specifically with CD4 + T cells, B cells, and myeloid-derived suppressor cells. Single-cell sequencing results indicated that the expression of S1PR4 was elevated in tumor cells of specific cancer types, such as GBM. In BRCA, S1PR4 coordinated an immunoregulatory network containing novel prognostic determinants.

Conclusion

These findings establish S1PR4 as a multifaceted regulator of tumor immunity and cancer pain, providing a dual-targeting strategy for precision oncology.