Endothelial indoleamine 2,3-dioxygenase 1 drives high-tryptophan diet-mediated thrombosis in cancer-bearing mice.

Authors

Asha Jose, Saran Lotfollahzadeh, Anna Natrakul, Arjun Patel, Kashvi Sethuraman, Kylla Przekop, Maria Del Carmen Piqueras, Arathi Ranga, Howard J Cabral, Nathanael Fillmore, Katya Ravid, Vipul C Chitalia

Published in

Blood vessels, thrombosis & hemostasis. Volume 3. Issue 4. Pages 100209. Epub Aug 28, 2026.

Abstract

Cancer-associated venous thromboembolism is a major cause of morbidity and mortality in patients with solid tumors and is driven, in part, by tumor-induced metabolic reprogramming. The tryptophan (Trp)-kynurenine (Kyn) pathway, regulated by indoleamine 2,3-dioxygenase 1 (IDO1), is frequently upregulated in cancer and generates bioactive metabolites with immunomodulatory and vascular effects. Although pharmacologic inhibition of IDO1 reduces thrombosis in tumor-bearing mice, the endothelial-specific contribution of IDO1 to cancer-associated thrombogenesis has not been genetically defined. Here, we used IDO1 global knockout and inducible IDO1 endothelial-specific knockout mice in a syngeneic MC38 tumor model combined with dietary Trp modulation to delineate the vascular role of IDO1. Global genetic deletion of IDO1 significantly reduced systemic Kyn accumulation and attenuated thrombus formation in the inferior vena cava of tumor-bearing mice. Endothelial-specific deletion of IDO1 led to reduced Kyn levels in the plasma, suppressed tumor-induced deep vein thrombosis, and downregulated expression of key prothrombotic mediators such as tissue factor, plasminogen activator inhibitor-1, and von Willebrand factor while preserving thrombomodulin expression. This suggested a selective amplification of procoagulant signaling by the Trp-IDO1-Kyn axis. Collectively, these findings provide direct genetic evidence that endothelial IDO1 is a contributing metabolic driver of cancer-associated thrombosis. Targeted control of the endothelial Trp-IDO1-Kyn pathway may represent a mechanistically informed strategy to mitigate thrombotic risk in patients with cancer.

PMID:
42904202
Bibliographic data and abstract were imported from PubMed on 23 Oct 2026.

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