Immunodynamic Disruption in Sepsis: Mechanisms and Strategies for Personalized Immunomodulation

Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection. It follows a dynamic course in which early hyperinflammation coexists and overlaps with progressive immune suppression, a process best described as immunodynamic disruption. Key mechanisms include extensive lymphocyte death, expansion of regulatory T cells, impaired antigen presentation, and persistent activation of inhibitory checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte–associated protein 4 (CTLA-4). These changes reduce immune competence and increase vulnerability to secondary infections. Clinically, reduced expression of Human Leukocyte Antigen–DR (HLA-DR) on monocytes and persistent lymphopenia have emerged as robust biomarkers for patient stratification and timing of immunomodulatory therapies. Beyond the acute phase, many survivors do not achieve full immune recovery but instead develop a Persistent Immune Remnant, defined as long-lasting immune, metabolic, and endothelial dysfunction despite apparent clinical resolution. Recognizing PIR emphasizes the need for long-term monitoring and biomarker-guided interventions to restore immune balance. To integrate these observations, we propose the SIMMP–Sepsis model (Sepsis-Associated Persistent Multiorgan Immunometabolic Syndrome), which links molecular dysfunction to clinical trajectories and provides a framework for developing precision immunotherapies. This perspective reframes sepsis not only as an acute crisis but also as a chronic immunometabolic syndrome, where survival marks the beginning of active immune restoration.