#3-56E. The Eye of the Storm: Unraveling PANoptosis and Targeted Therapies (Nat Rev Dis Primers, 2026)

From the lethal complications of sepsis to the toxicities of CAR-T cell therapy, managing hyperinflammatory syndromes is a high-stakes challenge in modern medicine. This primer provides a comprehensive update on "cytokine storm," defining it not just as an excess of cytokines, but as a self-amplifying positive feedback loop involving inflammatory cell death, or PANoptosis. The authors elucidate how triggers like infections or autoimmune conditions initiate a cascade where the synergism of TNF and IFNγ drives this lytic cell death, releasing further danger signals that perpetuate the storm. While this mechanistic clarity points toward promising interventions, physicians must remain cognizant of a critical limitation: the continued lack of standardized, unified diagnostic criteria across different underlying etiologies, which can delay life-saving treatment. For the clinician, this review is vital for navigating the expanding arsenal of targeted immunomodulators—such as anti-IL-6 receptor antibodies and JAK inhibitors—offering a roadmap to intercept this lethal cycle and prevent multiorgan failure in critically ill patients.

Citation: Karki, R., Netea, M. G., Diorio, C. & Kanneganti, T. D. Cytokine storm. Nature Reviews Disease Primers. 2026. DOI: 10.1038/s41572-025-00677-4

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