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Intratumoral delivery of synthetic STING agonists induces IFN-I\u2013dependent tumor regression in preclinical cancer models and is being tested clinically. In this study, we investigate the role of monocytic lineage cells (MCs) in response to STING agonist induced IFN-I signaling. We show that CCR2-deficient mice, lacking inflammatory MCs in the periphery, or Lyz2-Cre-IFNAR1fl\/fl mice in which IFN-I signaling in monocytes is reduced, exhibit impaired responses to STING agonist therapy of MC38 and\/or B16F10 tumors. STING agonist treatment induced CCR5-dependent migration of MCs carrying tumor antigen from the tumor to the lymph nodes. Single-cell RNA sequencing of CD45+ cells from lymph nodes and tumors of mice in which half the hematopoietic cells lack the IFNAR1 (interferon alpha\/beta receptor 1) revealed that STING agonist therapy induces intrinsic IFNAR1-dependent acquisition of an inflammatory monocytic cell phenotype distinct from inflammatory classical dendritic cells (cDC) and a reduction in macrophages with a protumor TGF\u03b2\/angiogenesis transcriptome. Interleukin (IL)-18\u2013IL-18R1 interaction was the top predicted interaction between monocytic lineage cells and CD8+ T cells or natural killer cells. Blocking IL-18 reduced IFN-\u03b3 production by CD8 T cells in lymph nodes and decreased the therapeutic efficacy of STING agonist treatment in Ccr2+\/+ but not in Ccr2\u2212\/\u2212 mice. These findings support a pivotal role for IL-18 producing inflammatory monocytic lineage cells in CD8+ T cell control of melanoma following STING agonist treatment.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf131","type":"journal-article","created":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T20:45:18Z","timestamp":1752093918000},"page":"3634-3646","source":"Crossref","is-referenced-by-count":8,"title":["STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity"],"prefix":"10.1093","volume":"214","author":[{"given":"Melanie","family":"Girard","sequence":"first","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianning","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia V","family":"Batista","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen K M","family":"Yeung","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lamorte","sequence":"additional","affiliation":[{"name":"Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoxi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy L","family":"McGaha","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, Ontario,","place":["Canada"]},{"name":"Tumor Immunotherapy Program, Princess Margaret Cancer Centre, University Health Network , Toronto, Ontario,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7897-4890","authenticated-orcid":false,"given":"Tania H","family":"Watts","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto , Toronto, 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