PD1 blockade-induced DKK1 expression by CD8+ T cells promotes blood-brain barrier permeabilization

Abstract Anti-PD1 therapy benefits a subset of brain metastasis (BrM) patients; 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. While anti-PD1 induced robust anti-tumor immune activation, it uniquely, among all ICIs tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8⁺ T cells through the induction of β-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma-DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, lung cancer patients receiving anti-PD1 exhibited increased MRI contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in non-responders. Sequencing anti-PD1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD1-induced BBB modulation as a tractable vulnerability in BrM management.