{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:11:07Z","timestamp":1793128267966,"version":"4.5.0"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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 (\u2018immunoparalysis\u2019) 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\u2014including assay standardization, harmonized thresholds for monocyte HLA-DR and whole-blood stimulation, and limited availability of clinically compatible spatial platforms\u2014that 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\u2013pathogen topology from FFPE-ready spatial assays, emerging strategies aim to restore antigen presentation, reconstitute priming, disrupt inhibitory myeloid\u2013lymphoid 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.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1696914","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T06:28:04Z","timestamp":1762324084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Decoding immune low-response states in sepsis: single-cell and 3D spatial transcriptomic insights into immunoparalysis"],"prefix":"10.3389","volume":"16","author":[{"given":"Yulian","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianying","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"eabe9599","DOI":"10.1126\/scitranslmed.abe9599","article-title":"Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro","volume":"13","author":"Reyes","year":"2021","journal-title":"Sci Trans Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s40779-023-00462-y","article-title":"Single-cell transcriptome profiling of sepsis identifies HLA-DR low S100A high monocytes with immunosuppressive function","volume":"10","author":"Yao","year":"2023","journal-title":"Military Med Res"},{"key":"B3","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s13054-024-04868-5","article-title":"Monocyte state 1 (MS1) cells in critically ill patients with sepsis or non-infectious conditions: association with disease course and host response","volume":"28","author":"Leite","year":"2024","journal-title":"Crit Care"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104363","article-title":"Immunopathophysiology of human sepsis","volume":"86","author":"Wiersinga","year":"2022","journal-title":"Ebiomedicine"},{"key":"B5","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13613-022-01010-y","article-title":"Monitoring of circulating monocyte HLA-DR expression in a large cohort of intensive care patients: relation with secondary infections","volume":"12","author":"de Roquetaillade","year":"2022","journal-title":"Ann Intensive Care"},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.1002\/cyto.b.22133","article-title":"Monocyte HLA-DR expression as an enrollment biomarker in sepsis clinical trials: Evaluation of two sampling tubes and definition of respective clinical thresholds. 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