Sepsis-induced PICS: Immunometabolic mechanisms, emerging biomarkers, and precision management

Sepsis, a life-threatening organ dysfunction caused by infection, casts a lingering shadow over its survivors. Many develop persistent inflammation, immunosuppression, and catabolism syndrome (PICS), a highly debilitating condition. Despite growing clinical recognition, the complex pathophysiology of PICS remains poorly understood. This review provides a comprehensive mechanistic framework for PICS by systematically synthesizing current knowledge and integrating cutting-edge insights from single-cell sequencing. We first examine the evolution and limitations of PICS diagnostic criteria. Subsequently, we dissect the key molecular and cellular mechanisms driving the core PICS triad: the critical role of pathogen- and damage-associated molecular patterns in sustaining persistent inflammation; the profound myeloid dysregulation and lymphoid exhaustion that collectively induce immunosuppression; and the mechanisms by which severe catabolism causes muscle wasting. Furthermore, we summarize the development of PICS animal models and their applications in mechanistic research. Finally, we evaluate emerging biomarkers for PICS diagnosis and review individualized therapeutic strategies targeting immunomodulation and metabolic support. By providing an integrated pathobiological framework, this review aims to accelerate the development of novel diagnostic tools and targeted interventions to improve long-term outcomes for sepsis survivors.