Sphingolipid metabolic subtyping defines SPHK1 as an oncogene and characterizes immunosuppressive TME features in gastric cancer.
4 affiliations
- 1Joint Laboratory of Biomedical Artificial Intelligence, Shanghai East Hospital, Tongji University School of Medicine, 200120, Shanghai, China.
- 2State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital Affiliated to Shanghai Jiao Tong University school of Medicine, Shanghai, 200127, China.
- 3Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation (CSRCT-SHANGHAI), Jiading District Central Hospital, Shanghai, 201800, China.
- 4Shanghai Key Laboratory of Cancer Systems Regulation and Clinical Translation, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, 201800, China. [email protected].
Abstract
Gastric cancer (GC) exhibits profound heterogeneity and poor clinical outcomes, underscoring the need for improved prognostic stratification and deeper insights into metabolism-immune interactions within the tumor microenvironment (TME). Although sphingolipid metabolic reprogramming is known to influence TME remodeling, systematic GC subtyping based on sphingolipid metabolism-related genes (SMGs) and the spatial regulatory roles of key metabolic enzymes remain insufficiently characterized. Using TCGA RNA sequencing data, we performed unsupervised clustering of SMGs and identified two metabolic subtypes. Cluster A was marked by upregulated sphingolipid metabolism, extensive extracellular matrix remodeling, and enrichment of immunosuppressive pathways, corresponding to significantly worse survival. Cluster B showed enrichment of energy metabolic programs and increased inflammatory immune infiltration, aligning with a more favorable prognosis. Spatial transcriptomic analysis revealed SPHK1 enrichment at the tumor invasive front, where high SPHK1 expression correlated with increased dendritic cell and neutrophil infiltration but not CD8⁺ T cell accumulation, suggesting a myeloid-dominant immunosuppressive niche. Functionally, SPHK1 knockdown suppressed GC cell proliferation and migration, increased E-cadherin, decreased mesenchymal markers, and inhibited TGF-β1 signaling, confirming its role in EMT and tumor progression. Collectively, these findings identify sphingolipid metabolic remodeling and aberrant SPHK1 activation as key drivers of GC immune evasion and potential therapeutic vulnerabilities.
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BibTeX
@article{wang2026sphingolipid,
title = {{Sphingolipid metabolic subtyping defines SPHK1 as an oncogene and characterizes immunosuppressive TME features in gastric cancer.}},
author = {Zeyu Wang and Zhuying Yue and Chengkai Jiang},
journal = {Cancer cell international},
year = {2026},
month = jul,
doi = {10.1186/s12935-026-04401-4},
url = {https://europepmc.org/article/MED/42908005},
note = {CC BY},
}
RIS
TY - JOUR
TI - Sphingolipid metabolic subtyping defines SPHK1 as an oncogene and characterizes immunosuppressive TME features in gastric cancer.
AU - Zeyu Wang
AU - Zhuying Yue
AU - Chengkai Jiang
PY - 2026
DA - 2026/07/01
JO - Cancer cell international
DO - 10.1186/s12935-026-04401-4
UR - https://europepmc.org/article/MED/42908005
AB - Gastric cancer (GC) exhibits profound heterogeneity and poor clinical outcomes, underscoring the need for improved prognostic stratification and deeper insights into metabolism-immune interactions within the tumor microenvironment (TME). Although sphingolipid metabolic reprogramming is known to influence TME remodeling, systematic GC subtyping based on sphingolipid metabolism-related genes (SMGs) and the spatial regulatory roles of key metabolic enzymes remain insufficiently characterized. Using TCGA RNA sequencing data, we performed unsupervised clustering of SMGs and identified two metabolic subtypes. Cluster A was marked by upregulated sphingolipid metabolism, extensive extracellular matrix remodeling, and enrichment of immunosuppressive pathways, corresponding to significantly worse survival. Cluster B showed enrichment of energy metabolic programs and increased inflammatory immune infiltration, aligning with a more favorable prognosis. Spatial transcriptomic analysis revealed SPHK1 enrichment at the tumor invasive front, where high SPHK1 expression correlated with increased dendritic cell and neutrophil infiltration but not CD8⁺ T cell accumulation, suggesting a myeloid-dominant immunosuppressive niche. Functionally, SPHK1 knockdown suppressed GC cell proliferation and migration, increased E-cadherin, decreased mesenchymal markers, and inhibited TGF-β1 signaling, confirming its role in EMT and tumor progression. Collectively, these findings identify sphingolipid metabolic remodeling and aberrant SPHK1 activation as key drivers of GC immune evasion and potential therapeutic vulnerabilities.
SN - 1475-2867
ER -