Immuno-Radiotherapy Enhances Tumor Control and Induces Abscopal Responses in a Humanized Mouse Model

Radiation therapy (RT) offers a tool to enhance immune checkpoint inhibitor (ICI) efficacy, yet its immunomodulatory potential remains poorly understood. Using a hematopoietic stem cell-humanized NOG mouse model bearing ICI-responsive renal cell carcinoma (RCC) or ICI-resistant non-small cell lung cancer (NSCLC) and melanoma, we reveal how RT dose-fractionation regimens shape local and systemic antitumor immunity. Immuno-RT (iRT) improved tumor control across models, and induced abscopal effects in ICI-resistant models, especially in NSCLC, where 3x8 Gy combined with ICI triggered systemic responses, increased circulating monocytes and remodeled the tumor microenvironment (TME). Flow cytometry, immunohistochemistry, and RNA-sequencing revealed dynamic immune remodeling, with late-stage responses in ICI-resistant tumors marked by low immune infiltration, high immune memory, cGAS/STING pathway, damage associated molecular patterns, cell death, and metabolic reprograming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.