STING agonists trigger monocyte death via apoptosis, pyroptosis, caspase-8 activation and mitochondrial dysfunction

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses double-stranded DNA in the cytoplasm, triggering the secretion of type I and III interferons and proinflammatory cytokines. However, cGAS-STING pathway activation by STING agonists also induces regulated cell death (RCD) in human monocytes, which is inherently linked to cytokine production. We identified that STING agonist-induced monocyte RCD integrates apoptotic (active caspase-9, -8 and -3/7) and pyroptotic mechanisms (active caspase-1, cleaved gasdermin-D and secreted mature interleukin-1β and -18), whereas necroptosis is inhibited through caspase-8-mediated cleavage of receptor-interacting protein kinase 1 (RIPK1). Additionally, this RCD is accompanied by mitochondrial dysfunction, which precedes caspase activation, suggesting that mitochondrial disruption may act as both the driving mechanism and a direct outcome of cGAS-STING pathway activation via the STING-IRF3-BAX pathway. Overall, this study identifies a novel RCD process that may be described as 'pyroptotic apoptosis', providing new insights into the outcomes of cGAS-STING signalling in human monocytes.