Aberrant lipid metabolism reshapes the immune landscape in bone metastasis of nasopharyngeal carcinoma.

BACKGROUND: Bone metastasis (BM) drives therapeutic resistance and mortality in nasopharyngeal carcinoma (NPC). Tumor metabolites are crucial for NPC metastasis; however, the mechanisms by which these metabolites synergistically alter the immune microenvironment to promote BM remain unclear. METHODS: In this study, limited immune infiltration was observed in the NPC BM tumor microenvironment. Multiomics analysis has identified sphingosine kinase 1 (SPHK1) as a pivotal mediator driving BM and immune evasion in NPC, orchestrating the production of 1-phosphorylated sphingosine (S1P), which is critical for NPC pathogenesis. RESULTS: The aberrant buildup of lipid metabolites, along with immune microenvironment shifts, serves as a critical driver of NPC BM. Mechanistically, S1P enhanced osteoclast recruitment via S1PR3 binding and activated the Hippo pathway, worsening bone colonization and facilitating immune evasion by expanding the exhausted CD8+ T cell population. CONCLUSIONS: The synergy between the SPHK1 inhibitor PF543 and anti-programmed cell death protein 1 therapy amplified treatment effectiveness beyond standalone approaches. Overall, the SPHK1/S1P pathway advances NPC growth and aids in suppressing immune defense. Regulation of lipid metabolism may be a therapeutic target against BM in NPC and may improve the effectiveness of immunotherapy.