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However, the mechanisms by which cGAS\u2010STING\u2010induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS\u2010STING signaling is identified to play a detrimental role in regulating anti\u2010malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria <jats:italic>Plasmodium yoelii nigeriensis<\/jats:italic> N67C infections by reducing late interleukin (IL)\u20106 production. Mechanistically, cGAS\/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38\u2010dependent signaling pathway for late IL\u20106 production, which, in turn, expands CD11b<jats:sup>+<\/jats:sup>Ly6C<jats:sup>hi<\/jats:sup> proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS\u2010STING\u2010MyD88\u2010p38\u2010IL\u20106 signaling axis or the depletion of CD11b<jats:sup>+<\/jats:sup>Ly6C<jats:sup>hi<\/jats:sup> proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria\u2010strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS\u2010STING\u2010MyD88\u2010p38 axis in infectious diseases through triggering the late IL\u20106 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.<\/jats:p>","DOI":"10.1002\/advs.202103701","type":"journal-article","created":{"date-parts":[[2022,5,29]],"date-time":"2022-05-29T22:17:35Z","timestamp":1653862655000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Activation of cGAS\u2010STING by Lethal Malaria N67C Dictates Immunity and Mortality through Induction of CD11b<sup>+<\/sup>Ly6C<sup>hi<\/sup> Proinflammatory Monocytes"],"prefix":"10.1002","volume":"9","author":[{"given":"Yang","family":"Du","sequence":"first","affiliation":[{"name":"Department of Medicine and 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