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To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. Although anti\u2013PD-1 induced robust antitumor immune activation, it uniquely, among all immune checkpoint inhibitors (ICI) tested, compromised blood\u2013brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8+ T cells through the induction of \u03b2-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\u2013PD-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\u2013PD-1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD-1\u2013induced BBB modulation as a tractable vulnerability in BrM management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>See related commentary by Karreman and Winkler, p. 831<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1222","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T21:42:52Z","timestamp":1768254172000},"page":"976-992","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PD-1 Blockade\u2013Induced DKK1 Expression by CD8+ T Cells Promotes Blood\u2013Brain Barrier 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