Multi-omics profiling reveals immune suppression and antigen presentation deficits following human spaceflight

Human spaceflight imposes unique physiological stressors that disrupt immune homeostasis, yet the molecular mechanisms underlying postflight immune dysfunction remain poorly understood. Here, we present an integrative, multi-omic secondary analysis of peripheral blood mononuclear cells (PBMCs) from the Inspiration4 mission [28] using publicly available data from NASA’s Open Scenc Data Repository (OSDR), integrating single-nucleus RNA sequencing (snRNA-seq), single-nucleus ATAC sequencing (snATAC-seq), and plasma proteomics. We identify broad transcriptional suppression of key antigen presentation genes—including HLA-A, HLA-B, HLA-C, and CD74—across multiple immune cell types postflight, with HLA-C showing the strongest reduction (log₂FC = –1.7, p < 0.01) in CD16⁺ monocytes. Concordant chromatin accessibility changes were observed in genes such as PDK4, CD86, and NR3C1, indicating epigenetic regulation of metabolic and immunomodulatory programs. Integration of matched snRNA-seq and snATAC-seq data revealed gene-specific coherence in transcriptional and epigenetic responses, particularly in monocytes. Proteomic validation using serum cytokine measurements from the NASA LSDS-8 Alamar panel confirmed statistically significant declines in circulating TGFB1 and CXCL2 (2.8% and 2.3% respectively, p < 0.05), aligning with transcriptional trends. Functional enrichment analysis highlighted postflight repression of interferon signaling, antigen processing, and glucocorticoid-responsive pathways. Given the small sample size (n=4), these findings should be considered preliminary but provide important proof-of-concept evidence for multi-layered immune suppression following spaceflight. Together, these findings delineate a multi-layered signature of immune suppression following spaceflight and establish a framework for cell-type–resolved, cross-platform immunomonitoring in future human missions.