ArticleCancer discovery2026
PD-1 Blockade-Induced DKK1 Expression by CD8+ T Cells Promotes Blood-Brain Barrier Permeabilization.
Article in Cancer discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed.
- Spatial Transcriptomics Reveals a T Cell-Mediated Microglial Activation Axis of Immune Checkpoint Inhibition-Related Adverse Events in the Brain.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- First-line serplulimab plus chemotherapy versus chemotherapy alone in small-cell lung cancer patients with brain metastases: a multicenter, prospective cohort study.Frontiers in immunology · 2026Article
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
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 β-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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