Immuno-radiotherapy enhances tumor control and induces abscopal responses in a humanized mouse model.

[INTRODUCTION] Radiation therapy (RT) offers a tool to enhance immune checkpoint inhibitor (ICI) efficacy, yet its immunomodulatory potential remains poorly understood. Here, we investigated how RT dose-fractionation regimens shape local and systemic antitumor immunity.

[METHODS] A hematopoietic stem cell-humanized NOG mouse model was established, bearing ICI-responsive renal cell carcinoma (RCC) or ICI-resistant non-small cell lung cancer (NSCLC) and melanoma. Mice were treated with RT using different dose-fractionation regimens in combination with ICI. Tumor growth, systemic immune responses, and abscopal effects were assessed. Immune remodeling was characterized by flow cytometry, immunohistochemistry, and RNA-sequencing analyses.

[RESULTS & DISCUSSION] 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). Late-stage responses in ICI-resistant tumors were marked by low immune infiltration but enriched signatures of immune memory, cGAS/STING pathway, damage associated molecular patterns, cell death, and metabolic reprogramming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.