SPHK1 promotes HNSCC immune evasion by regulating the MMP1-PD-L1 axis

<b>Rationale:</b> Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy against head and neck squamous cell carcinoma (HNSCC), but their overall response rate (ORR) remains limited. Previous studies have highlighted the crucial role of sphingosine kinases (SPHKs) in the tumor microenvironment (TME); however, their function in immunotherapy remains unclear. <b>Methods:</b> We conducted comprehensive bioinformatics analysis, functional studies, and clinical validation, to investigate the role of SPHK1 in the immunology of HNSCC. <b>Results:</b> Functionally, SPHK1 significantly promoted tumor growth by inhibiting anti-tumor immunity in immune-competent HNSCC mouse models and tumor-T cell co-cultures. Mechanistic analysis revealed that SPHK1 regulated matrix metalloproteinase-1 (MMP1) expression via the MAPK1 pathway, which subsequently influenced tumor programmed cell death ligand 1 (PD-L1) expression. Furthermore, SPHK1 and MMP1 could predict the efficacy of programmed cell death 1 monoclonal antibody (PD-1 mAb) immunotherapy in HNSCC and were independent risk factors for survival in patients with HNSCC. <b>Conclusion:</b> Our study reveals a novel role for SPHK1 in mediating immune evasion in HNSCC through the regulation of the MMP1-PD-L1 axis. We identified SPHK1 and MMP1 as predictive biomarkers for the therapeutic response to PD-1 mAb and provided new therapeutic targets for patients with HNSCC.