What is it about?
Radiotherapy kills cancer cells, but it does not work for large tumors or teaches the immune system to keep fighting the cancer. In this work, we focus on a special type of cancer cell death called immunogenic cell death (ICD). When cancer cells die in certain ways, e.g., by radiation, dying tumor cells release signals that activate the immune system to attack the remaining cancer. We built a mathematical model that connects radiation dose, tumor growth, macrophages (the immune cells that “eat” cancer cells), and ICD. The model is calibrated and tested against mouse data from therapies that block the SIRPα-CD47 “don’t-eat-me” signal on tumor cells. This blockade makes macrophages more ready to eat cancer cells and can trigger stronger systemic immune responses. Our simulations show that radiation alone does not trigger much ICD. But when we combine radiation with macrophage-based immunotherapy that blocks SIRPα-CD47, ICD increases dramatically, meaning that we have both direct cancer killing and strong immune system activation. The model also predicts an optimal range of radiation doses (about 6–8 Gy) that maximizes ICD and a dose-dependent abscopal effect, where treating one tumor site can shrink tumors at distant sites by activating the immune system. We also show that macrophages engineered or selected to lack SIRPα may be among the most powerful options in this combination.
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Photo by National Cancer Institute on Unsplash
Why is it important?
Immunotherapy has transformed cancer treatment, but many patients still do not respond, and radiotherapy is often used without a clear strategy for engaging the immune system. A key challenge is understanding how much radiation to give and how to combine it with immunotherapy. Our study provides a quantitative framework for answering these questions. By linking preclinical data to a mechanistic mathematical model, this research provides a recipe for doctors to design better combination treatments. Instead of guessing at doses and timing, we now have mathematical predictions for how to maximize the benefits of combining radiation with immune therapy.
Perspectives
What I find most satisfying about this work is its simplicity: we built a minimal, rigorous mathematical model, adding each component only when the experimental data required it. Despite its simplicity, the model can reproduce and connect diverse experimental findings from multiple laboratories. By clarifying the links between radiation, macrophages, and immunogenic cell death, our model moves us beyond trial-and-error combinations and toward a mechanism-guided design of radiation--immunotherapy strategies.
Yi Jiang
Georgia State University
Read the Original
This page is a summary of: Immunogenic cell death unlocks the potential for combined radiation and immunotherapy, Proceedings of the National Academy of Sciences, November 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2509875122.
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