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.