MINI REVIEW article
Front. Immunol.
Sec. Systems Immunology
This article is part of the Research TopicExploring immune low-response states through single-cell technologies and spatial transcriptomicsView all 28 articles
Decoding Immune Low-Response States in Sepsis: Single-Cell and 3D Spatial Transcriptomic Insights into Immunoparalysis
Provisionally accepted
- 1The Second People’s Hospital of Deyang, Deyang, China
- 2The Affiliated Hospital of Southwest Medical University, Luzhou, China
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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 summarise 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 programmes, and appraise translational opportunities spanning endotype-guided risk stratification, pharmacodynamic monitoring and spatial biomarkers.. We also discuss enduring challenges—including assay standardisation, harmonised 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 endeavour to convert descriptive immune low-response states into tractable, reversible clinical entities.
Keywords: Sepsis, Immunoparalysis, Immune low-response states, monocyte HLA-DR, Endotoxin tolerance, single-cell RNA sequencing
Received: 01 Sep 2025; Accepted: 21 Oct 2025.
Copyright: © 2025 Yang, Yi, Wu, Liu and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xianying Lei, leixianyin310@swmu.edu.cn
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