Involvement of Kynurenine Pathway in Hepatocellular Carcinoma

Simple Summary The kynurenine pathway (KP) is a biochemical pathway that synthesizes the vital coenzyme, nicotinamide adenine dinucleotide (NAD(+)). In cancer, the KP is significantly activated, leading to tryptophan depletion and the production of downstream metabolites, which skews the immune response towards tumour tolerance. More specifically, advanced stage cancers that readily metastasize evidence the most dysregulation in KP enzymes, providing a clear link between the KP and cancer morbidity. Consequently, this provides the rationale for an attractive new drug discovery opportunity for adjuvant therapeutics targeting KP-mediated immune tolerance, which would greatly complement current pharmacological interventions. In this review, we summarize recent developments in the roles of the KP and clinical trials examining KP inhibition in liver cancer. As the second and third leading cancer-related death in men and the world, respectively, primary liver cancer remains a major concern to human health. Despite advances in diagnostic technology, patients with primary liver cancer are often diagnosed at an advanced stage. Treatment options for patients with advanced hepatocarcinoma (HCC) are limited to systemic treatment with multikinase inhibitors and immunotherapy. Furthermore, the 5-year survival rate for these late-stage HCC patients is approximately 12% worldwide. There is an unmet need to identify novel treatment options and/or sensitive blood-based biomarker(s) to detect this cancer at an early stage. Given that the liver harbours the largest proportion of immune cells in the human body, understanding the tumour-immune microenvironment has gained increasing attention as a potential target to treat cancer. The kynurenine pathway (KP) has been proposed to be one of the key mechanisms used by the tumour cells to escape immune surveillance for proliferation and metastasis. In an inflammatory environment such as cancer, the KP is elevated, suppressing local immune cell populations and enhancing tumour growth. In this review, we collectively describe the roles of the KP in cancer and provide information on the latest research into the KP in primary liver cancer.

Automated summary

The kynurenine pathway is significantly activated in cancer, leading to immune tolerance towards tumors. Liver cancer remains a major concern as the second and third leading cancer-related deaths in men and worldwide, respectively. Early detection and novel treatment options are urgently needed.