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

Growing evidence indicates that immunological and metabolic outcomes are key mediators of long-term high-altitude exposure (LTHAE) adaption, but the underlying mechanisms remain poorly understood. This study employs plasma metabolomics and peripheral blood single-cell transcriptomic sequencing to analyze the metabolic and immune dynamic regulation in 46 young male lowlanders following a 90-day adaptation period at high altitude. Single-cell analysis shows a pattern of “innate immune activation and adaptive immune suppression” under LTHAE, characterized by facilitated maturation of neutrophils, enhanced cytotoxicity of CD56 ^dim NK cells, and increased immune responsiveness of cDC2 and pDC, while inhibited maturation of plasmablasts and suppressed immune responsiveness of CD8□TEM and CD4 ⁺ T cells. Plasma metabolic analysis reveals significant alterations, involving enhanced steroid hormone synthesis, unsaturated fatty acid and amino acid metabolism under LTHAE, which in turn are associated with immune remodeling. Moreover, transcriptomic-metabolic integration analysis indicates the molecular mechanisms of enhanced aerobic oxidation efficiency under LTHAE. Collectively, these findings provide integrated insights into immune-metabolic landscape remodeling and suggest potential mutual regulatory relationship between immune and metabolic state following LTHAE, offering a molecular foundation for high-altitude adaptation research.