Abstract 1832: Identifying GSK3b inhibitor as a radiation induced type I interferon stimulator in lung cancer

Radiation therapy (RT) is commonly used to treat multiple tumor types to reduce the risk of tumor recurrence. Despite impressive clinical responses only a subset of patients responds to RT, due to the lack of an adequate immune response within lung tumors. There is a strong motivation to develop novel approaches to overcome immunosuppression in tumors after radiation therapy. Here, we aim to identify pathways that could specifically augment type I interferon (IFN) response with RT to bypass the immune suppressive effects. We combined radiation and >700 pharmacological inhibitors in a high throughput screen to identify agents that induced type I IFN response. We revealed a GSK3β inhibitor (GSK3βi), Kenpaullone, as a drug hit that induced synergistic response with RT to enhance type I IFN expression. The selected GSK3βi was validated for its IFNβ1 induction in the mRNA and protein levels in multiple lung cancer cell lines, and by examining the associated AKT/GSK3β/IRF3 pathway. The effectiveness of this unique GSK3βi-RT combination to enhance IFNβ1 immunologic stimulation was tested in syngeneic tumor bearing animals and significantly reduced tumors size compared to radiation or drug alone. COMET analysis from mice tumors showed that combination therapy increased T cells and M1 macrophages at the tumor microenvironment (TME), while M2 macrophages and PDL-1 decreased. This pharmacological-RT combination approach has the potential to enhance the immunologic response to RT in lung cancer patients to reduce tumor burden in those that already exhausted standard of care therapies. Citation Format: Chen Braun, Nan Li, Steven H. Lin. Identifying GSK3b inhibitor as a radiation induced type I interferon stimulator in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1832.