Background <p>High-altitude de-acclimatization (HADA) is accompanied by a complex spectrum of long-term physiological and functional remodeling processes, potentially affecting long-term health outcomes. Existing studies on HADA have predominantly focused on cardiovascular and nervous system changes. However, the immune system—an essential regulator of disease susceptibility, inter-individual variability, and long-term health risks—remains insufficiently investigated in the context of HADA.</p> Aims <p>Given the central role of immune regulation in maintaining systemic homeostasis and determining individual health trajectories, elucidating immune alterations associated with HADA is essential. The present study aims to characterize immune system remodeling during HADA with particular emphasis on its functional outcomes and mechanisms. By addressing these scientific questions, this study seeks to provide an immune system perspective for the health maintenance of HADA individuals, promoting paradigm shift from reactive medical services toward predictive, preventive, and personalized medicine (3PM).</p> Methods <p>Peripheral blood was collected from both human cohorts and mice models while other immune organs including spleen, thymus and bone marrow were obtained from mice models. Proportions of immune cell populations in peripheral blood and other immune organs were analyzed using flow cytometry. The immune-suppressive functions of Tregs were determined by in vitro co-culture with CD8⁺ T cells. Transcriptomic and chromatin-accessibility feature induced by HADA were obtained through RNA-seq and ATAC-seq.&#xa0;The functional validation of HADA target gene was performed using specific agonist during in vitro co-culture system.</p> Results <p>HADA perturbed the proportions of immune populations in multiple immune site. Both data from human and mice showed increased regulatory T cells (Tregs) and enhanced immune-suppressive function in the peripheral blood. As a consequence, these Tregs mediated long-term immune suppression and compromised the immunity against tumor cells. Multi-omic analyses predicted Nrf2 as the key mediator of molecular alterations in Tregs caused by HADA, which was further confirmed by the functional assay.</p> Conclusion and expert recommendation <p>This study advances high-altitude medicine by demonstrating that HADA induces long-lasting immunosuppressive effects through Nrf2-mediated Treg remodeling, with important implications for immune homeostasis and long-term health risks. These findings highlight the role of the immune system, particularly Tregs, in HADA-induced health impairments and identify Nrf2 as a potential therapeutic target. Moreover, immune biomarkers—especially Treg phenotypes and Nrf2 activity—may serve as promising candidates for risk stratification and predictive diagnostics in populations transitioning between high- and low-altitude environments. Preventive strategies should prioritize immune-informed recovery protocols, oxidative stress modulation, and lifestyle or nutritional interventions tailored to individual immune profiles.</p>