Abstract C027: STING-mediated Myeloid Reprogramming Drives Immunotherapy Response in DNA Repair Mutant Tumors

Abstract Immune checkpoint blockade (ICB) has shown unprecedented success in improving clinical outcomes for cancer patients, but many patients still fail to respond to treatment. Studies by us and others have demonstrated that DNA Damage Repair (DDR) pathways play a key role in determining response to ICB. More granular assessment shows that certain DDR alterations are more immunogenic both due to increased antigenic burden as well as facilitating a more permissive tumor microenvironment (TME). Using an isogenic BRCA2 knockout breast cancer murine model, we show that BRCA2-deficient tumors exhibit distinct tumor-intrinsic inflammation, characterized by cytosolic DNA and R-loops that synergistically drive trans-activation of the myeloid interferon response via cGAS/STING. Interrogation of the TME revealed a reprogrammed myeloid landscape with elevated ISG expression and T cell-recruiting chemokines. Interferon reporter assay results suggested tumor-intrinsic cGAS drives trans-activation of myeloid STING and IFNb1. While tumor-intrinsic STING signaling was dispensable for ICB response, monocyte depletion via CSF1R blockade or myeloid-specific STING deletion abrogated response, demonstrating the essential role of myeloid cells. ISG+ monocyte repolarization and ICB response was lost with cytoplasmic DNA and RNA degradation within tumor cells. Importantly, targeted delivery of STING agonists to myeloid populations converted wildtype tumors to ICB responsive. Taken together, our work emphasizes the importance of tumor-myeloid crosstalk and how DDR alterations may differentially poise the microenvironment for immunotherapy response via myeloid repolarization. Strategies to enhance “DDR-like” phenotypes via monocyte repolarization may promote ICB response. Citation Format: Natalie Vaninov, Robert M. Samstein. STING-mediated Myeloid Reprogramming Drives Immunotherapy Response in DNA Repair Mutant Tumors [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C027.