The Role of STING-Mediated Activation of Dendritic Cells in Cancer Immunotherapy

Ana RS Ribeiro,1,2 Theresa Neuper,1– 3 Jutta Horejs-Hoeck1– 3 1Department of Biosciences and Medical Biology, Paris Lodron University of Salzburg, Salzburg, Austria; 2Cancer Cluster Salzburg (CCS), Salzburg, 5020, Austria; 3Center for Tumor biology and Immunology (CTBI), Salzburg, 5020, AustriaCorrespondence: Jutta Horejs-Hoeck, Department of Biosciences and Medical Biology, Paris-Lodron University Salzburg, Hellbrunner Strasse 34, Salzburg, 5020, Austria, Tel +43(0)662 8044 5709, Email [email protected]: The signaling pathway that comprises cyclic guanosine monophosphate–adenosine monophosphate (cGAMP or GMP-AMP) synthase (cGAS) and Stimulator of Interferon Genes (STING) is emerging as a druggable target for immunotherapy, with tumor-resident dendritic cells (DC) playing a critical role in mediating its effects. The STING receptor is part of the DNA-sensing cellular machinery, that can trigger the secretion of pro-inflammatory mediators, priming effector T cells and initiating specific antitumor responses. Yet, recent studies have highlighted the dual role of STING activation in the context of cancer: STING can either promote antitumor responses or enhance tumor progression. This dichotomy often depends on the cell type in which cGAS-STING signaling is induced and the activation mode, namely acute versus chronic. Of note, STING activation at the DC level appears to be particularly important for tumor eradication. This review outlines the contribution of the different conventional and plasmacytoid DC subsets and describes the mechanisms underlying STING-mediated activation of DCs in cancer. We further highlight how the STING pathway plays an intricate role in modulating the function of DCs embedded in tumor tissue. Additionally, we discuss the strategies being employed to harness STING activation for cancer treatment, such as the development of synthetic agonists and nano-based delivery systems, spotlighting the current techniques used to prompt STING engagement specifically in DCs.Keywords: dendritic cell, cGAS-STING pathway, cancer immunotherapy, nanoparticle