Abstract Mechanisms of defense against nucleic acids are central to maintaining genome integrity and have evolved to sense multiple nucleic acids alterations in structure and/or location within a cell. In cancer, dysregulation of DNA repair pathways and gene transcription are common and are associated with cellular stress and innate immune signaling, thus promoting immune surveillance. Subversion of such responses is often required for a cancer to evade immune control and progress to become clinically significant. One example is the epigenetic silencing of stimulator of interferon genes (STING), which is activated by cGAMP produced by the cyclic GMP-AMP synthase (cGAS) after sensing cytosolic DNA. Importantly, therapeutic interventions, such as radiation therapy, can leverage these hard-wired nucleic acids defense pathways to induce anti-tumor immune responses. Extensive preclinical data demonstrate that induction of interferon type I (IFN-I) in cancer cells and the tumor microenvironment by radiation promotes antigen presentation and recruitment of T cells and plays a central role in the ability of radiation to synergize with immune checkpoint inhibitors. In the clinic, however, such effects of radiation have not been consistently observed in unselected patient populations. This highlights the need for an improved understanding of the complex cross-talk between radiation-induced DNA damage response and innate immune signaling, and their alterations in cancer. We are currently investigating the interplay between cGAS/STING pathway and the ectonucleotidases that convert pro-inflammatory signals generated by radiation into immunosuppressive adenosine. The latter offers candidate actionable targets to improve radiation-induced immune activation. Overall, insights into the fundamental mechanisms that couple DNA damage with innate immune signaling will enable the fine tuning of therapeutic interventions that promote anti-tumor immune responses. Citation Format: Sandra Demaria. Therapeutic modulation of nucleic acids-induced immune activation abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr IA03.
Sandra Demaria (Wed,) studied this question.