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Purpose Cancer remains to be a leading cause of death worldwide, accounting for almost 10 million deaths in 2018. Radiation therapy (RT) is a common nonsurgical treatment in the management of patients with cancer that reduces disease recurrence and improves overall survival. However, preclinical RT modeling for accelerated bench-to-bedside translation of combination therapies is largely missing. While genetically engineered mouse models (GEMM) faithfully recapitulate human disease, conventional linear particle accelerator systems, commonly utilized in clinical settings, are not suited for state-of-the-art, image-guided targeted RT (IGRT) of these murine autochthonous tumors. Thus, we employed the CyberKnife (Accuray) platform for IGRT of GEMM-derived non-small cell lunger cancer (NSCLC) lesions. The CyberKnife (CK) is a stereotactic radiosurgery system (SRS) delivering high-dose RT precisely to the target area with minimal damage to the surrounding tissues based on intra-fraction image-guidance. Material and methods GEMM-derived NSCLC flank tumors driven by oncogenic Kras (KrasLSL-G12D/+) and deletion of Tp53 (Trp53fl/fl) were irradiated using the CK RT platform. We applied IGRT of 2, 4, 6, and 8 Gy using field sizes of 5 to 12.5 mm to average gross tumor volumes (GTV) of 0.9 cm3 (minimal 0.03 cm3) using Xsight Spine Tracking (Accuray) spine-based tumor localization. Results We found that a 0 mm planning target volume (PTV) margin is sufficient for IGRT of murine tumors using the CK. Furthermore, we analyzed the impact of CK-mediated IGRT on tumor infiltrating leukocytes by flow cytometry. We observed that higher RT doses (6-8 Gy) decreased absolute cell numbers of lymphocytes and myeloid cells by approximately half compared to low doses (2-4 Gy) or mock treated tumors within one hour, but even with low dose RT (2 Gy) tumor infiltrating leukocytes (TIL) were found to be reduced after 8 to 24 hours and recovered partly after 3 days. Conclusion In summary, we here demonstrate that the CK RT system allows for targeted IGRT of murine tumors with high precision and thus constitutes a novel promising platform for translational mouse RT studies, particularly performed in a longitudinal multimodal manner.