Remodeling of the immune-metabolic landscape triggered by long-term high-altitude exposure

Immunometabolic remodeling drives adaptation to long-term high-altitude exposure (LTHAE), yet the underlying mechanisms remain elusive. By integrating single-cell transcriptomics and metabolomics from 46 lowlanders following a 90-day LTHAE, we identified a strategy of "innate activation and adaptive suppression." Neutrophils exhibited enhanced maturation and phagocytosis, whereas adaptive immunity was dampened, characterized by suppressed B cell function and T cell responsiveness. Metabolically, LTHAE induced systemic shifts in steroid and amino acid metabolism associated with immune remodeling. Furthermore, multi-omics integration indicated a conserved upregulation of the glycolysis-TCA-OXPHOS axis across immune lineages, a metabolic adaptation supported by enzymatic assays in hematopoietic tissues of a hypobaric hypoxia mouse model. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest a potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.