ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Immuno-Radiotherapy Enhances Tumor Control and Induces Abscopal Responses in a Humanized Mouse Model
Morgane M. Cogels 1,2
Matteo Serra 2
Hugues Duvillier 2
Soizic Garaud 2
Laurine Verset 1
David Venet 2
Chrysanthi Iliadi 1,2
Tycho de Bakker 1
Laurence Buisseret 2
Redouane Rouas 1
Christos Sotiriou 2
Françoise Rothé 2
Alex de Caluwé 2
Dirk Van Gestel 1
Sébastien Penninckx 1,2
1. Institut Jules Bordet, Université libre de Bruxelles, Anderlecht, Belgium
2. Universite Libre de Bruxelles, Brussels, Belgium
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Abstract
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 reprogramming. Our findings support RT as a strategy to overcome ICI resistance and validate humanized mice as a translational model for iRT research.
Summary
Keywords
abscopal effect, humanized mice, Immunotherapy, Radiotherapy, Tumor immune microenvironment
Received
24 December 2025
Accepted
20 February 2026
Copyright
© 2026 Cogels, Serra, Duvillier, Garaud, Verset, Venet, Iliadi, de Bakker, Buisseret, Rouas, Sotiriou, Rothé, de Caluwé, Van Gestel and Penninckx. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sébastien Penninckx
Disclaimer
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