Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in
preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized
the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understand-
ing of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable
targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models
of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases
as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to
revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary mela-
noma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with
clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively,
we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer
that balances therapeutic benefit and toxicity