A single-cell transcriptomic atlas reveals the immune panorama of neonatal sepsis.

Neonatal sepsis remains a leading cause of infant mortality, yet mechanisms driving concurrent hyperinflammation and immunosuppression remain unclear. Here, we perform single-cell RNA sequencing on 26 blood samples from 18 neonates, spanning acute sepsis, convalescence, and healthy controls. We identify 57 cell subtypes, revealing acute lymphoid depletion and myeloid expansion. S100A8+ myeloid-derived suppressor cell-like (MDSC-like) cells represent a putative cytokine-storm source, potentially amplified by a feedforward S100-TLR4-MYD88 circuit. Innate-like lymphocytes fail to expand, succumbing to apoptosis and exhaustion despite heightened cytotoxicity. CD4+ T cells display mitochondrial dysfunction, while regulatory T cells acquire a hyper-suppressive phenotype via the LGALS9-HAVCR2 axis. CD8+ T cells undergo interferon-driven, innate-like reprogramming before lapsing into exhaustion, and B cells shift toward stress-adaptive, tolerogenic states. Together, our atlas defines a dual pathology in which MDSC-like cell-driven cytokine storm coexists with multi-lineage immunoparalysis, nominating the S100-TLR4 axis and mitochondrial dysregulation as potential therapeutic targets.