Cytokine storm.

Cytokine storm describes a spectrum of clinical manifestations that feature increased cytokine levels in circulation owing to overactivated immune responses. These increased concentrations of cytokines can cause tissue and organ damage, potentially leading to lethality. Cytokine storm can be induced by a variety of underlying clinical conditions, including infection, auto-inflammatory and autoimmune conditions, monogenic causes, or therapeutic intervention, which often makes diagnosis and treatment difficult. However, studies have identified conserved molecular mechanisms that inform therapeutic strategies. Cytokine storm is initiated by cytokine production and exacerbated by a self-amplifying positive feedback loop between cytokines and inflammatory cell death (PANoptosis). The process begins when cells detect triggers and undergo inflammatory signalling to produce and release cytokines via canonical secretion pathways or through lytic cell death such as pyroptosis and PANoptosis. This release of inflammatory cytokines, and potentially of other damage-associated molecules, can then drive inflammation and cell death in neighbouring cells through paracrine PANoptosis, resulting in further cytokine release and the amplification of the cycle. Improved understanding of the molecular and cellular mechanisms driving cytokine storm is critical for developing effective therapeutic strategies and improving clinical outcomes.