Multi-omics profiling reveals sphingolipid metabolism reprogramming of tumor-conditioned MDSCs in cervical cancer

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) play a crucial role in the tumor microenvironment (TME) of cervical cancer (CC), yet the mechanisms underlying their reprogramming remain poorly understood. METHODS: To explore the immune microenvironment change in CC, we applied TCGA-CC immune microenvironment infiltration estimation analysis via Timer 2.0 online datasets. To generate tumor-conditioned MDSCs, the culture medium of MDSCs was supplemented with supernatants from the murine CC cell lines U14 and TC1, respectively. CCK8 assays, transwell migration experiments and qPCR were executed to test the proliferation, migration and iNOS expression. We then conducted proteomics and metabolomics analyses of tumor-conditioned MDSCs. RESULTS: The tumor immune microenvironment analysis identified MDSCs as key components, predicting poor prognosis in CC. Tumor-conditioned MDSCs presented higher proliferation, migration and iNOS expression. Proteomics and metabolomics analyses showed significant changes in lipid metabolism, especially sphingolipid metabolism. Specifically, the Kng1-sphingosine 1-phosphate axis was identified as a central protein-metabolite regulatory node. Gain- and loss-of-function experiments confirmed that KNG1 modulates multiple cellular processes including proliferation, migration, iNOS expression, and sphingosine 1-phosphate production. CONCLUSION: Our findings uncover sphingolipid metabolic reprogramming as a key mechanism in MDSCs-mediated immune suppression, and propose the Kng1-sphingosine 1-phosphate network as a potential therapeutic target for CC treatment.