Abstract B012: Interferon- γ is required for immunotherapy induced radiosensitivity in solid tumors

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Abstract Radiation therapy (RT) is the standard of care for many cancer types, however, some solid tumors fail to respond due to factors such as a hypoxic tumor microenvironment (TME). To overcome radioresistance in these solid tumors, clinical trials combining RT with immune checkpoint blockade (ICB) are ongoing, but hindered by a limited understanding of the mechanisms by which immunotherapies enhance RT response. In this study, we use EO771 breast and CT26 colorectal tumor models to investigate how anti PD-1 therapy improves radiosensitivity to varying RT regimens including single or multiple RT doses administered concurrently or sequentially. We show that concurrent administration of ICB and RT normalizes tumor vasculature, alleviates hypoxia, and increases vessel perfusion to improve immune cell infiltration in solid tumors. Furthermore, we reveal that this TME modulation was linked to stimulation of interferon-γ (IFN-γ) signaling in endothelial cells by activated CD8+ T cell responses, which results in systemic tumor control and establishes long term immunological memory in the neoadjuvant setting. Collectively, these results indicate that immunotherapy sensitizes solid tumors to RT by modulating the tumor microenvironment in an IFN-γ dependent manner, resulting in successful anti-tumor immunity. This research provides a rationale for the concurrent administration of anti PD-1 therapy and radiation therapy to treat radioresistant solid tumors. Citation Format: Annette Wu, Minjeong Kang, Daeyong Lee, Yifan Wang, Kristin M. Huntoon, Betty Y.S. Kim, Wen Jiang. Interferon- γ is required for immunotherapy induced radiosensitivity in solid tumors. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B012.