Emanuele Lettera, PhD, Postdoctoral Fellow Memorial Sloan Kettering Cancer Center Activation of the immune system is an important consequence of normal and tumor tissue exposure to cancer treatments such as chemotherapy, ionizing radiation, and targeted agents. Recent evidence suggests that activation of the cytosolic DNA sensing cGAS-STING pathway plays an important role in anti-tumor immunity and that this pathway is required for the therapeutic effects of radiotherapy and immune checkpoint inhibitors. While acute cGAS-STING-mediated inflammatory response impart an anti-tumor effect, chronic tumor inflammation has been associated with disease progression, therapeutic resistance, immune suppression, and metastasis. Tumors with unstable chromosomes display a chronic inflammatory scenario due to persistent activation of cGAS-STING signaling. These aggressive tumors develop mechanisms to escape from immune surveillance and adopt metastatic behaviors. A more thorough understanding of the mechanisms regulating cGAS-STING pathway and its downstream mediators is needed to fully harness the potential of this pathway during immunotherapy treatments. Dr. Lettera’s proposal is based on the finding that repetitive – or chronic – stimulation from elevated cGAS activity can lead to rapid desensitization of interferon signaling, which is central to a productive and coordinated anti-tumor immune response, increased STING degradation, and alteration of endoplasmic reticulum (ER)-stress in normal fibroblasts and in chromosomally unstable cancer cells. The goal of this proposal is to identify and target potential drivers of STING-mediated interferon signaling suppression and reprogram tumor microenvironment through inhibition or attenuation of STING-dependent ER stress response. These findings will offer an exciting opportunity for therapeutic intervention given ongoing efforts to develop selective targets of STING pathway and ER-stress sensors inhibitors. Projects and Grants Therapeutic targeting STING-mediated tumor inflammation induced by Chromosomal Instability Memorial Sloan Kettering Cancer Center | All Cancers | 2022 | Samuel, Bakhoum, M.D., Ph.D.