Endothelial indoleamine 2,3-dioxygenase 1 drives high-tryptophan diet-mediated thrombosis in cancer-bearing mice.
7 affiliations
- 1Department of Medicine, Renal Section, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
- 2Department of Chemistry, Boston University, Boston, MA.
- 3Department of Biostatistics, School of Public Health, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
- 4Veterans Affairs Boston Healthcare System, Boston, MA.
- 5Department of Medicine and Whitaker Cardiovascular Institute, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
- 6Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA.
- 7Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA.
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.
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BibTeX
@article{jose2026endothelial,
title = {{Endothelial indoleamine 2,3-dioxygenase 1 drives high-tryptophan diet-mediated thrombosis in cancer-bearing mice.}},
author = {Asha Jose and Saran Lotfollahzadeh and Anna Natrakul and Arjun Patel and Kashvi Sethuraman and Kylla Przekop and Maria Del Carmen Piqueras and Arathi Ranga and Howard J Cabral and Nathanael Fillmore and Katya Ravid and Vipul C Chitalia},
journal = {Blood vessels, thrombosis \& hemostasis},
year = {2026},
month = aug,
doi = {10.1016/j.bvth.2026.100209},
url = {https://europepmc.org/article/MED/42904202},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Endothelial indoleamine 2,3-dioxygenase 1 drives high-tryptophan diet-mediated thrombosis in cancer-bearing mice.
AU - Asha Jose
AU - Saran Lotfollahzadeh
AU - Anna Natrakul
AU - Arjun Patel
AU - Kashvi Sethuraman
AU - Kylla Przekop
AU - Maria Del Carmen Piqueras
AU - Arathi Ranga
AU - Howard J Cabral
AU - Nathanael Fillmore
AU - Katya Ravid
AU - Vipul C Chitalia
PY - 2026
DA - 2026/08/28
JO - Blood vessels, thrombosis & hemostasis
DO - 10.1016/j.bvth.2026.100209
UR - https://europepmc.org/article/MED/42904202
AB - 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.
SN - 2950-3272
ER -