Abstract
Cancer remains a major global health challenge, with incidence and mortality rates continuing to rise. Metabolic reprogramming, a hallmark of cancer, not only sustains rapid proliferation but also shapes an immunosuppressive tumor microenvironment. Among metabolic enzymes, sphingosine kinase 1 (SPHK1) plays a key role in sphingolipid signaling by regulating the balance between sphingosine-1-phosphate and sphingosine. This regulation influences both cell fate and immune responses. However, the role of SPHK1 as a potential “metabolic immune checkpoint” across various cancers, as well as its implications for prognosis and immunotherapy, remains insufficiently explored. In this pan-cancer study, we analyzed SPHK1 expression using RNA-seq data from The Cancer Genome Atlas, which includes 33 cancer types. We also examined its clinical association. We then validated SPHK1 expression at the mRNA and protein levels in clinical samples of head and neck squamous cell carcinoma (HNSC), stomach adenocarcinoma (STAD), and liver hepatocellular carcinoma (LIHC) using RT‑qPCR and immunohistochemistry, and assessed its effect on cancer cell viability using the CCK‑8 assay. Furthermore, we conducted integrated analyses to evaluate the relationship between SPHK1 expression and key immunological features, including immune cell infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint gene expression. These analyses aimed to delineate SPHK1’s role in immune modulation. We observed significant upregulation of SPHK1 in multiple cancers, especially in HNSC, STAD, and LIHC. We also confirmed its ability to enhance cancer cell viability. High SPHK1 expression is consistently associated with poor patient survival, supporting its prognostic value. Importantly, comprehensive immunological analyses revealed that SPHK1 expression is closely linked to immunosuppressive features across cancers, including altered immune cell infiltration and elevated expression of established immune checkpoint molecules, positioning SPHK1 as a key regulator linking metabolic dysregulation to immune evasion. Our findings suggest that SPHK1 acts as an oncogene and prognostic biomarker. Additionally, it functions as a novel “metabolic immune checkpoint” across multiple cancer types. SPHK1 may bridge sphingolipid metabolism with tumor immune suppression and represents a potential promising integrated target for metabolically informed immunotherapy strategies.
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Data availability
The data used for bioinformatic analyses during the current study are original from public databases, including The Cancer Genome Atlas (TCGA) (available at https://portal.gdc.cancer.gov/), the Human Protein Atlas (HPA) (accessible at https://www.proteinatlas.org/), The cBioPortal platform (available at https://www.cbioportal.org/), The UALCAN database (http://ualcan.path.uab.edu/), BioGRID (https://thebiogrid.org/), STRING(https://cn.string-db.org/), GDSC (https://www.cancerrxgene.org/), CTRP (https://portals.broadinstitute.org/ctrp/) and CellMiner (https://discover.nci.nih.gov/cellminer/home.do).The data used for the validation experiment are available from the corresponding author upon reasonable request. All scripts and processed data matrices for this study were uploaded to a public GitHub repository accessible via the following link: https://github.com/xhbuestc/SPHK1-pan-cancer-analysis/tree/main/Code; https://github.com/xhbuestc/SPHK1-pan-cancer-analysis/tree/main/Processed%20matrics.
Abbreviations
- ACC :
-
Adrenocortical carcinoma
- BLCA:
-
Bladder urothelial carcinoma
- BRCA:
-
Breast invasive carcinoma
- CESC:
-
Cervical squamous cell carcinoma and endocervical adenocarcinoma
- CHOL:
-
Cholangiocarcinoma
- COAD:
-
Colon adenocarcinoma
- DLBC:
-
Lymphoid neoplasm diffuse large B-cell lymphoma
- ESCA:
-
Esophageal carcinoma
- GBM:
-
Glioblastoma multiforme
- HNSC:
-
Head and neck squamous cell carcinoma
- KICH:
-
Kidney chromophobe
- KIRC:
-
Kidney renal clear cell carcinoma
- KIRP:
-
Kidney renal papillary cell carcinoma
- LAML:
-
Acute myeloid leukemia
- LGG:
-
Brain lower grade glioma
- LIHC:
-
Liver hepatocellular carcinoma
- LUAD:
-
Lung adenocarcinoma
- LUSC:
-
Lung squamous cell carcinoma
- MESO:
-
Mesothelioma
- OV:
-
Ovarian serous cystadenocarcinoma
- PAAD:
-
Pancreatic adenocarcinoma
- PCPG:
-
Pheochromocytoma and paraganglioma
- PRAD:
-
Prostate adenocarcinoma
- READ:
-
Rectum adenocarcinoma
- SARC:
-
Sarcoma
- SKCM:
-
Skin cutaneous melanoma
- STAD:
-
Stomach adenocarcinoma
- TGCT:
-
Testicular germ cell tumors
- THCA:
-
Thyroid carcinoma
- THYM:
-
Thymoma
- UCEC:
-
Uterine corpus endometrial carcinoma
- UCS:
-
Uterine carcinosarcoma
- UVM:
-
Uveal melanoma
- OS:
-
Overall survival
- DSS:
-
Disease specific survival
- PFI:
-
Progress free interval
- GO:
-
Gene ontology
- KEGG:
-
Kyoto encyclopedia of genes and genomes
- IHC :
-
Immunohistochemistry
- ROC:
-
Receiver operating characteristic
- GDSC:
-
Genomics of drug sensitivity in cancer
- CTRP:
-
The cancer therapeutics response portal
- Cor:
-
Correlation coefficient
- TCGA:
-
The cancer Genome atlas
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Acknowledgements
We thank The Cancer Genome Atlas (TCGA) (available at https://portal.gdc.cancer.gov/), the Human Protein Atlas (HPA) (accessible at https://www.proteinatlas.org/), the cBioPortal platform (available at https://www.cbioportal.org/), the UALCAN database (http://ualcan.path.uab.edu/), BioGRID (https://thebiogrid.org/), STRING (https://cn.string-db.org/), KEGG (www.kegg.jp/kegg/kegg1.html), GDSC (https://www.cancerrxgene.org/), CTRP (https://portals.broadinstitute.org/ctrp/) and CellMiner (https://discover.nci.nih.gov/cellminer/home.do) for providing open datasets for the analyses.
Funding
This study was supported by Sichuan Science and Technology Program (grant number: 2025ZNSFSC0577); Technology Innovation Research and Development Project of Chengdu Science and Technology Bureau (grant number: 2021-YF05-02064-SN); the healthy department of Sichuan Province (grant number: 20PJ116); Fujian Provincial Natural Science Foundation of China (Grant number: 2024J01644); The major Science and Technology Planning Project of Jingmen City, Hubei Province, China (Grant Number: 2023YFZD033).
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Qiuju Wang: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing Original Draft, Writing—review & editing, Funding acquisition; Lei Wang: Methodology, Validation, Formal analysis, Investigation, Data curation, Writing—review & editing, Visualization, Funding acquisition; Guodong Zhong: Methodology, Validation, Formal analysis, Investigation, Software, Data curation, Writing—review & editing. Hao Luo and Qiao He: Validation, Formal analysis, Investigation, Resources, Data curation, Visualization. Yan Chen: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data curation, Writing—review & editing, Visualization, Project administration; Wei Li: Methodology, Validation, Formal analysis, Writing—review & editing, Funding acquisition.
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Wang, L., Zhong, G., Luo, H. et al. The emerging role of SPHK1 at the immune-metabolic interface: a pan-cancer integrative analysis. Sci Rep (2026). https://doi.org/10.1038/s41598-026-35350-7
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DOI: https://doi.org/10.1038/s41598-026-35350-7
