High-altitude exercise orchestrates a divergent immune landscape: cytotoxic suppression, humoral compensation, and neutrophil functional reprogramming.

Physical exertion at high-altitude imposes a dual stress of hypoxia and mechanical load, yet the underlying immune adaptations remain poorly understood. Plasma proteomics and single-cell RNA sequencing were performed in 46 healthy men undergoing standardized exercise at low and high altitudes, and the findings were validated in mice exposed to chronic extreme hypoxia (simulated 5,800 m) combined with exhaustive exercise. Whereas broad immune activation was induced by low-altitude exercise, cytotoxic and innate effector programs in CD8 T cells, natural killer cells, monocytes, and dendritic cells were broadly suppressed following high-altitude exercise. In contrast, humoral immunity was enhanced, as indicated by the activation of plasmablasts and CD4 memory and proliferating T cells. Mature neutrophils were functionally reprogrammed toward phagocytosis and degranulation, accompanied by an expansion of activated circulating neutrophils. A high-altitude-specific program involving chemotaxis and vascular extravasation was further identified by plasma proteomic and murine muscle transcriptomic analyses. These adaptations were associated with enhanced APRIL, MIF, and Annexin A1 signaling and attenuated CCL-chemokine and complement pathways. Collectively, high-altitude exercise was shown to induce coordinated immune reconfiguration characterized by cellular immunosuppression, selective humoral enhancement, and neutrophil-mediated tissue infiltration.