Insufficient erythrocyte-derived S1P: A pathogenic driver and diagnostic biolipid for tumor progression

Erythrocytes are the sole oxygen (O₂) transporters and highly sensitive hypoxia responders, yet their active role in tumor development remains unclear. Here, we identify a compensatory erythrocyte adaptation to hypoxia that enhances O₂ release in head and neck squamous cell carcinoma (HNSCC). Untargeted metabolomics revealed a 13-metabolite erythrocyte signature with diagnostic potential, with sphingosine emerging as a central metabolic node altered across erythrocytes, plasma, and tumors. Erythrocytes from patients with HNSCC exhibited metabolic reprogramming characterized by increased sphingosine and sphingosine kinase 1 (SPHK1)-dependent sphingosine-1-phosphate (S1P) production, together with loss of the S1P transporter major facilitator superfamily domain-containing protein 2B (MFSD2B), resulting in systemic sphingolipid imbalance. Genetic ablation of erythrocyte-specific SPHK1 disrupted O₂ and S1P release, impaired angiogenesis, and promoted an immunosuppressive tumor microenvironment, thereby accelerating tumor growth. These findings establish erythrocytes as active metabolic regulators of tumor progression via SPHK1/S1P signaling.