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Decoding immune low-response states in sepsis: single-cell and 3D spatial transcriptomic insights into
Yulian Yang1,2, Yi Zhang1, Jingjing Wu1
1Department of Critical Care Medicine, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
Frontiers in Immunology
|November 21, 2025
Summary
Sepsis causes immune suppression (immunoparalysis), hindering therapies. New single-cell and spatial techniques reveal immune cell states, offering precision medicine strategies to reverse these low-response states and improve patient outcomes.
Area of Science:
- Immunology
- Critical Care Medicine
- Genomics
Background:
- Sepsis is a major global cause of critical illness with limited durable benefit from current immune-directed therapies.
- Immune responses in sepsis are heterogeneous, often characterized by immune suppression ('immunoparalysis') affecting both innate and adaptive immunity.
- Existing treatments lack efficacy due to this immune heterogeneity, necessitating novel therapeutic approaches.
Purpose of the Study:
- To review advances in single-cell and spatial transcriptomics for understanding sepsis-induced immune dysfunction.
- To identify translational opportunities for precision medicine in sepsis based on immune endotypes.
- To discuss challenges and propose standards for implementing immunoparalysis-informed strategies.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) and ATAC sequencing (scATAC-seq) to profile immune cell states.
- Immune repertoire assays to analyze adaptive immune responses.
- 3D spatial transcriptomics to map immune cell interactions within tissues.
- Integration of functional assays (e.g., HLA-DR, cytokine production) with multi-omic data.
Main Results:
- Detailed characterization of monocyte, dendritic cell (cDC1, cDC2, pDC), lymphocyte, and NK cell programs in sepsis.
- Identification of distinct immune endotypes, including S100A-high monocytes and checkpoint-biased T cells.
- Demonstration of potential for spatial biomarkers in FFPE tissues for host-pathogen interactions.
- Highlighting challenges in assay standardization and clinical platform availability.
Conclusions:
- Precision medicine for sepsis can be advanced by integrating functional bedside data with single-cell and spatial immune profiling.
- Emerging strategies aim to restore immune function, reconstitute immune priming, and prevent secondary infections.
- Development of composite biomarkers and standardized decision rules is crucial for clinical implementation of immunoparalysis-informed therapies.
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