Decoding immune low-response states in sepsis: single-cell and 3D spatial transcriptomic insights into immunoparalysis.

Sepsis remains a leading cause of critical illness worldwide. Despite advances in supportive care, durable benefit from immune-directed therapies is limited, reflecting heterogeneity with immune low-response states ('immunoparalysis') across innate and adaptive compartments. In this review we summarize advances from single-cell RNA and ATAC profiling, immune-repertoire assays and 3D spatial transcriptomics that resolve monocyte, dendritic-cell (cDC1, cDC2 and pDC), lymphocyte and NK-cell programs, and appraise translational opportunities spanning endotype-guided risk stratification, pharmacodynamic monitoring and spatial biomarkers. We also discuss enduring challenges-including assay standardization, harmonized thresholds for monocyte HLA-DR and whole-blood stimulation, and limited availability of clinically compatible spatial platforms-that temper implementation. By integrating bedside function (HLA-DR trajectories, LPS-induced cytokine capacity) with single-cell endotypes (MS1/HLA-DR^low S100A^high monocytes, dendritic-cell attrition, checkpoint-biased T cells) and host-pathogen topology from FFPE-ready spatial assays, emerging strategies aim to restore antigen presentation, reconstitute priming, disrupt inhibitory myeloid-lymphoid circuits and prevent secondary infection. Our synthesis provides an appraisal of the evolving landscape of immunoparalysis-informed precision medicine in sepsis and outlines pragmatic standards for composite biomarkers, patient selection and on-therapy decision rules. We hope these insights will assist investigators and clinicians as they endeavor to convert descriptive immune low-response states into tractable, reversible clinical entities.