Kynurenine promotes angiogenesis through mTOR signaling in head and neck squamous cell carcinoma

Abstract Angiogenesis and its maturation play a crucial role in the progression and prognosis of head and neck squamous cell carcinoma (HNSCC). Tumor growth relies on an adequate blood supply to meet metabolic demands, while metabolic reprogramming within the tumor microenvironment actively reshapes vascular architecture. Meanwhile, the tumor microenvironment induces metabolic reprogramming that reshapes the vasculature. Alterations in tryptophan metabolism have been observed in HNSCC, with kynurenine (Kyn) significantly elevated in cancer tissues. Although Kyn has been reported to regulate vascular function in several diseases, its role in angiogenesis in HNSCC remains unclear. Metabolic profiling assessed alterations in tryptophan metabolism in HNSCC. Transcriptomic data from the TCGA HNSCC cohort were analyzed to examine correlations between IDO1 expression and angiogenesis-related genes. These findings were validated in tumor specimens from 28 HNSCC patients via immunohistochemistry. Based on these clinical observations, functional and mechanistic studies were conducted using human umbilical vein endothelial cells (HUVECs) and the chick embryo chorioallantoic membrane (CAM) model to evaluate the effects of Kyn on endothelial migration, angiogenic capacity, and neovascularization. A subcutaneous cell-derived xenograft (CDX) mouse model was further employed to assess the association between IDO1 expression and vascular markers in vivo. The involvement of IDO1-mediated Kyn production and mTOR signaling activation was further investigated. Tryptophan metabolism was markedly reprogrammed in HNSCC, with significantly elevated levels of Kyn in tumor tissues. Analysis of the TCGA HNSCC cohort revealed that IDO1, the key enzyme responsible for kynurenine production, was positively correlated with multiple angiogenesis-related genes. Immunohistochemical analysis revealed a positive correlation between IDO1 expression and endothelial markers CD31 and CD34 in patient samples, suggesting a potential link between Kyn and tumor angiogenesis. Consistently, Kyn enhanced endothelial cell migration and tube formation in vitro and promoted neovascularization in the CAM model. In line with these findings, analysis of tumor tissues from the CDX mouse model demonstrated positive correlations between IDO1 expression and multiple vascular markers, including CD31, CD34, and CD105. Mechanistically, IDO1-driven Kyn production activated the mTOR pathway in endothelial cells, leading to the upregulation of angiogenesis-related genes, pro-angiogenic factors, and their receptors. These findings reveal a novel pro-angiogenic role of Kyn in HNSCC, mediated through IDO1-dependent tryptophan metabolism and mTOR pathway activation. Targeting tryptophan metabolism may provide a potential therapeutic strategy for highly vascularized HNSCC.