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Pick the radiation dose that switches the immune alarm on, not off

Radiation can alert the immune system, but too big a single dose destroys the very alarm signal it creates. Picking the right dose and schedule may be free extra benefit.

Single fractions above roughly 12-18 Gy induce the DNA exonuclease TREX1, which degrades cytoplasmic DNA and prevents cGAS-STING activation, whereas fractionated schedules around 8 Gy times three maximise interferon signalling in mouse models. Radiotherapy plus immunotherapy trials have used dose and fractionation chosen for tumour control or convenience, not for immune priming, which may explain inconsistent abscopal results.

Hypothesis
Immune-optimised fractionation produces higher intratumoural interferon signatures and more abscopal responses than a single high-dose fraction in patients receiving concurrent checkpoint blockade, at equal local control.
Rationale
The TREX1 threshold effect is one of the few quantitative dose-response rules in immuno-radiobiology, and it is directly testable in humans with biopsy transcriptomics. Radiotherapy schedules cost nothing to change.
What would test it
A randomised biomarker trial of single high-dose versus immune-optimised fractionation to an index lesion with concurrent checkpoint blockade; primary endpoint the interferon-stimulated gene signature in a non-irradiated lesion.
Maturity
preclinical evidence
Who has to act
clinic
Cost to try
Medium ($1M to $50M)
Years to first evidence
5
Bottlenecks it attacks

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