Anti-PD-1 therapy benefits a subset of patients with brain metastasis (BrM); however, heterogeneous responses imply an incomplete understanding of the brain-immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. Although anti-PD-1 induced robust antitumor immune activation, it uniquely, among all immune checkpoint inhibitors (ICI) tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8+ T cells through the induction of beta-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, patients with lung cancer receiving anti-PD-1 exhibited increased magnetic resonance imaging contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in nonresponders. Sequential administration of anti-PD-1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD-1-induced BBB modulation as a tractable vulnerability in BrM management. SIGNIFICANCE: Our study demonstrates that PD-1 blockade induces DKK1 expression in activated CD8+ T cells, leading to BBB permeabilization. This previously unrecognized host-driven mechanism may explain heterogeneous intracranial responses to immunotherapy and identifies BBB modulation as a therapeutic opportunity to enhance drug delivery and efficacy for BrM. See related commentary by Karreman and Winkler, p. 831.
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