COUP-TFII-mediated reprogramming of the vascular endothelium counteracts tumor immune evasion

Yu Zhu (), Kevin F. Brulois, Thanh T. Dinh, Junliang Pan and Eugene C. Butcher ()
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Yu Zhu: Stanford University School of Medicine
Kevin F. Brulois: Stanford University School of Medicine
Thanh T. Dinh: Stanford University School of Medicine
Junliang Pan: Stanford University School of Medicine
Eugene C. Butcher: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract T cell scarcity in tumor tissues poses a critical challenge to cancer immunotherapy. Here we manipulate the tumor vasculature, an essential regulator of immune cell trafficking, to reinvigorate anti-tumor T cell responses in “cold” tumors. We show that ectopic pan-endothelial expression of COUP-TFII, a master transcription factor for venous development, induces molecular programs of post-capillary venules in tumor endothelium. Venular reprogramming selectively promotes T cell recruitment into tumors, inhibits tumor growth in mouse models of breast and pancreatic cancers, and sensitizes tumors to immune checkpoint blockade and adoptive T cell transfer therapies. Mechanistic studies show that enhanced recruitment of anti-tumor T cells and tumor inhibition are mediated by COUP-TFII-induced vascular adhesion receptors. Our study supports a pivotal role of vascular endothelial cells in governing tumor immune evasion, and proposes venular reprogramming as a therapeutic strategy to bolster anti-tumor immunity and immunotherapy.

Date: 2025
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DOI: 10.1038/s41467-025-62399-1

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