Aberrant STAT signaling and T cell dysregulation define a targetable pediatric sepsis endotype.

Summary

Prospective multi-omics profiling of 88 critically ill children identified an IL-6/IFN-γ–driven hyperinflammatory endotype with T cell dysfunction and baseline STAT1/3 hyperactivation that failed to respond to TCR stimulation. These convergent data nominate the JAK/STAT pathway as a rational immunomodulatory target in pediatric sepsis.

Key Findings

• Unsupervised cytokine clustering revealed three subgroups; the highest severity group was driven by IL-6 and IFN-γ hypercytokinemia.
• CD8+ T cells in the high-severity group showed baseline STAT1/STAT3 hyperactivation and failed to respond to αCD3/αCD28/αCD49d stimulation.
• Single-cell RNA-seq demonstrated suppression of a lymphoid protective gene program across CD8+ subsets with bystander activation and no dominant clonotypes.
• Data converge on the JAK/STAT axis as a targetable pathway in a defined pediatric sepsis endotype.

Clinical Implications

Supports immune endotyping to stratify pediatric sepsis and provides a rationale to test JAK/STAT inhibitors or IL-6–targeted strategies in biomarker-enriched trials.

Limitations

• Single-cohort sample size of 88 limits generalizability and statistical power for subgroup analyses
• Observational design without interventional validation of JAK/STAT targeting

Future Directions

Biomarker-driven interventional trials of JAK/STAT inhibitors or IL-6/IFN-γ modulation in the Group C endotype, with external validation cohorts.