Sepsis is a systemic inflammatory response syndrome triggered by infection. It presents with simultaneous overactive immune activation and immune paralysis, leading to a cytokine storm, tissue injury, and multiple organ failure. The molecular mechanisms and pathological characteristics of the septic cytokine storm are comprehensively interpreted from multiple perspectives, including immune regulation, signaling pathways, cellular interactions, metabolic state reprogramming, and microcirculatory dysfunction. The cross-activation of signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinase (MAPK), and NLRP3 inflammasome, underlies the core mechanism for the enhancement of the inflammatory response via continued release of proinflammatory cytokines and also is involved in maintaining immune balance. In the latestage immunosuppressive phase, Treg cells, myeloid-derived suppressor cells (MDSCs) and regulatory macrophages play pivotal roles in reestablishing host homeostasis through negative feedback, and their dysfunction is closely associated with secondary infections and high mortality. This review consolidates the latest developments in precision medicine and multidimensional biomarkers, emphasizing the prospective value of several markers such as lactate and CD64, pentraxin 3 (PTX3), and BMP9 for early diagnosis and rognosis evaluation. Moreover, it reviews novel immunomodulators, for instance, bee venom peptides, GDF15, N-(1,3,4-oxadiazol-2-yl) guanidine (NWG), 4-octyl itaconate  (4-OI), and nanoparticle drug delivery systems that inhibit inflammatory signaling cascades, restore energy metabolism, and provide organ protection. Taken together, the pathogenic mechanisms of sepsis are non-linear and dynamic, which may render single-target therapy insufficient for successful management. Personalized interventions targeting multi-target network regulation based on omics and AI models may accomplish precision monitoring and stratified treatment of inflammatory responses, also providing new theoretical and clinical strategies to reduce sepsis-related mortality.