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Systemic delivery of STING agonists to tumor-resident myeloid cells will be required to elicit optimal type I interferon-mediated anti-tumor immunity in a metastatic disease setting. To this end, we have generated a microbial-based immunotherapy (STACT- Salmonella Typhimurium (Attenuated) Checkpoint Therapy) that utilizes a highly attenuated, clinically developed strain that is specifically enriched in tumors after intravenous administration. The strain has been modified to reduce pro-inflammatory TLR signaling in order to limit its immunosuppressive microbial profile and significantly improve its therapeutic index. An inhibitory microRNA to TREX1 was designed and introduced into the STACT strain. TREX1 is a 3′ exonuclease immune checkpoint that degrades cytosolic DNA, thereby preventing it from binding cGAS and activating the STING pathway. Mutations in human TREX1 cause a type I interferonopathy known as Aicardi-Goutières syndrome and autoimmune chilblain lupus. Systemic delivery of small-molecule inhibitors targeting TREX1 are intractable due to its ubiquitous expression in healthy tissue. We have engineered our systemically administered therapy to specifically deliver RNAi against TREX1 to the myeloid compartment of the tumor microenvironment, rather than to the inflammatory TNFα- and IL-6-producing stromal compartment. This enables targeted cGAS/STING induction of type I interferon, thereby promoting optimal T cell priming against tumor neoantigens. STACT-TREX1 was evaluated for therapeutic efficacy in several tumor models, including CT26 and MC38 colon carcinoma models, and B16.F10 melanoma. A high degree of tumor-specific colonization of STACT-TREX1 therapy was observed after a single intravenous tail vein administration, with 100,000-fold enrichment detected in tumor tissue relative to spleen and liver. The therapy was well tolerated, with very low TNFα and IL-6 serum cytokines detected. In multiple flank tumor models, potent tumor growth inhibition and complete tumor regressions were observed as a monotherapy. Efficacy was CD8-dependent, and cured mice were protected from tumor re-challenge. Importantly, immune correlates post-treatment demonstrated a significant shift away from the recruitment of microbe-induced innate myeloid populations, and towards type I interferon-induced adaptive immunity. This novel therapeutic approach will allow for systemic delivery of a STING pathway agonist that induces type I interferon specifically in tumor-resident myeloid cells, inducing potent adaptive anti-tumor immunity in solid tumors that are refractory to existing immunotherapies. Citation Format: Anastasia M. Makarova, Alexandre Iannello, Chris S. Rae, Beverly King, Marina Besprozvannaya, John Faulhaber, Justin Skoble, Christopher D. Thanos, Laura Hix Glickman. STACT-TREX1: A systemically-administered STING pathway agonist targets tumor-resident myeloid cells and induces adaptive anti-tumor immunity in multiple preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5016.