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

Source: https://onco.cc/ideas/idea-bio2-radiotherapy-sting-fractionation/  
OnCo record `idea-bio2-radiotherapy-sting-fractionation` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Radiation can alert the immune system through the cGAS-STING pathway, but single doses above roughly 12 to 18 Gy switch on the enzyme TREX1, which destroys the alarm signal. Choosing fractionated schedules around 8 Gy times three for immune priming may add benefit at no extra cost.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed test: 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
- Actor: clinic

## Sources

- Bottleneck evidence (Cold tumours and the immunosuppressive microenvironment): Haslam & Prasad, Estimation of the percentage of US patients eligible for and responding to checkpoint inhibitors (JAMA Netw Open 2019): https://doi.org/10.1001/jamanetworkopen.2019.2535

## Connected records

- pairings: [Radiotherapy + immunotherapy](https://onco.cc/pairings/radiation-plus-io/)
- technologies: [FLASH radiotherapy](https://onco.cc/technologies/flash-rt/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/)
- pathways: [cGAS-STING innate sensing](https://onco.cc/pathways/cgas-sting/)
- terms: [Abscopal effect](https://onco.cc/terms/abscopal-effect/), [Immunogenic cell death](https://onco.cc/terms/immunogenic-cell-death/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/), [Surgery and radiotherapy cure most, get least](https://onco.cc/bottlenecks/b-surgery-radiation-innovation/)
- key papers: [Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs](https://onco.cc/key-papers/paper-haslam-jama-netw-open/)
- roadmaps: [Radiotherapy roadmap: X-rays → shaped beams → fewer fractions, particles and FLASH](https://onco.cc/roadmaps/radiation-roadmap/)

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