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

## TL;DR

This study shows that combining radiation therapy with immune treatments can control tumors and trigger immune responses in resistant cancers using humanized mice.

## Contribution

The study demonstrates that immuno-radiotherapy can overcome ICI resistance and validates humanized mice as a translational model for this approach.

## Key findings

- Immuno-RT improved tumor control and induced abscopal effects in ICI-resistant models.
- The 3x8 Gy regimen combined with ICI triggered systemic immune responses and TME remodeling in NSCLC.
- Late-stage responses showed immune memory and metabolic reprogramming in resistant tumors.

## Abstract

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.

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.

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.