PANoptosis

PANoptosis is an inflammatory cell death pathway. Genetic, molecular, and biochemical studies identified extensive crosstalk among the molecular components across cell death pathways in response to a variety of pathogens and innate immune triggers, leading to the conceptualization of PANoptosis.[1][2] PANoptosis is defined as a unique innate immune inflammatory cell death pathway driven by caspases and RIPKs and regulated by multi protein PANoptosome complexes. PANoptosis is implicated in driving innate immune responses and inflammation in disease. PANoptosome formation and PANoptosis occur during pathogenic infections, including bacterial, viral, and fungal infections, as well as during inflammatory diseases and can be beneficial in the context of cancer.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]

Inflammatory cell death is associated with activation of the immune system through the release of cytokines and damage-associated molecular patterns. Live pathogens that carry multiple pathogen-associated molecular patterns and homeostasis-altering triggers can modulate cell death pathways. Pyroptosis (inflammatory caspase-mediated cell death that drives maturation of the cytokines IL-1β and IL-18) and necroptosis (RIPK1/RIPK3/MLKL-driven cell death) were historically described as two major inflammatory cell death pathways, with recent studies describing PANoptosis as an additional inflammatory cell death pathway.

Activation of PANoptosis can clear infected cells for host defense, and it has shown preclinical promise as an anti-cancer strategy. For example, PANoptosis is important for host defense during influenza infection through the ZBP1-PANoptosome and during Francisella and herpes simplex virus 1 infections through the AIM2-PANoptosome.[3][5][16][17] Additionally, treatment of cancer cells with the PANoptosis-inducing agents TNF and IFN-γ[4][11] can reduce tumor size in preclinical models.[10] The combination of the nuclear export inhibitor selinexor and IFN can also cause PANoptosis and regress tumors in preclinical models.[1][18] However, excess activation of PANoptosis can be associated with inflammation, inflammatory disease, and cytokine storm syndromes.[4][9][19][14][15] Treatments that block TNF and IFN-γ to prevent PANoptosis have provided therapeutic benefit in preclinical models of cytokine storm syndromes, including cytokine shock, SARS-CoV-2 infection, sepsis, and hemophagocytic lymphohistiocytosis,[11] suggesting the therapeutic potential of modulating this pathway.[4] Further studies with beta-coronaviruses have shown that IFN can induce ZBP1-mediated PANoptosis during SARS-CoV-2 infection, thereby limiting the efficacy of IFN treatment during infection and resulting in morbidity and mortality. This suggests that inhibiting ZBP1 may improve the therapeutic efficacy of IFN therapy during SARS-CoV-2 infection and possibly other inflammatory conditions where IFN-mediated cell death and pathology occur.[2][12] More recent evidence suggests that NLRP12-mediated PANoptosis is activated by heme, which can be released by red blood cell lysis during infection or inflammatory disease, in combination with specific components of infection or cellular damage.[14][15] Deletion of NLRP12 protects against pathology in animal models of hemolytic disease, suggesting this could also act as a therapeutic target.[14][15]