The Immunological Landscape of Sepsis: From Cytokine Storm to Immune Paralysis

Abstract

Background: Sepsis is a dynamic and heterogeneous syndrome characterized by a dysregulated host response to infection, leading to concurrent hyperinflammation and profound immunosuppression. Early recognition of pathogen- and damage-associated molecular patterns triggers extensive activation of NF-κB, JAK/STAT, and MAPK pathways, resulting in a cytokine storm, metabolic reprogramming, and endothelial dysfunction. Mitochondrial impairment, glycocalyx degradation, and excessive neutrophil activity further propagate organ injury and microcirculatory collapse. Simultaneously, widespread apoptosis and exhaustion of lymphocytes culminate in immune paralysis and increased susceptibility to secondary infections. Advances in transcriptomics, proteomics, metabolomics, and machine-learning–based classification have uncovered distinct immune endotypes of sepsis, providing the foundation for precision medicine. Emerging immunomodulatory therapies—including IL-7, GM-CSF, and immune checkpoint inhibitors—aim to restore immune function in selected subgroups. Ultimately, sepsis must be viewed as a multifaceted immunometabolic disorder requiring individualized diagnosis, monitoring, and treatment approaches.