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bioRxiv · 10.1101/2025.02.14.638342

Immunogenic Cell Death: the Key to Unlocking the Potential for Combined Radiation and Immunotherapy

Rauf, S.·Smirnova, A.·Chang, A.·Liu, Y.·Jiang, Y.
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Abstract

Immunogenic cell death (ICD) enhances anti-tumor immunity by releasing tumor-associated antigens and activating the anti-tumor immune system response. However, its potential remains understudied in combination therapies. Here, we develop a mathematical model to quantify the role of ICD in optimizing the efficacy of combined radiotherapy (RT) and macrophage-based immunotherapy. Using preclinical murine data targeting the SIRP-CD47 checkpoint, we show that RT alone induces minimal ICD, whereas disrupting the SIRP-CD47 axis significantly enhances both phagocytosis and systemic immune activation. Our model predicts an optimal RT dose (6-8 Gy) for maximizing ICD, a dose-dependent abscopal effect, and a hierarchy of treatment efficacy, with SIRP-knockout macrophages exhibiting the strongest tumoricidal activity. These findings provide a quantitative framework for designing more effective combination therapies, leveraging ICD to enhance immune checkpoint inhibition and radiotherapy synergy.

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Rauf, S., Smirnova, A., Chang, A., Liu, Y., Jiang, Y.. 2025-02-17. Immunogenic Cell Death: the Key to Unlocking the Potential for Combined Radiation and Immunotherapy. https://doi.org/10.1101/2025.02.14.638342

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