The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

SIMPLE SUMMARY: The kynurenine pathway has two main physiological roles: (i) it protects specific organs such as the eyes and placenta from strong immune reactions and (ii) it additionally generate in the liver and kidney a metabolite essential to all cells of human body. Abnormal activation of this pathway is recurrently observed in numerous cancer types. Its two functions are hijacked to promote tumor growth and cancer cell dissemination through multiple mechanisms. Clinical assays including administration of inhibitors of this pathway have not yet been successful. The complex regulation of this pathway is likely the reason behind this failure. In this review, we try to give an overview of the current knowledge about this pathway, to point out the next challenges, and to propose alternative therapeutic routes. ABSTRACT: The kynurenine pathway has been highlighted as a gatekeeper of immune-privileged sites through its ability to generate from tryptophan a set of immunosuppressive metabolic intermediates. It additionally constitutes an important source of cellular NAD(+) for the organism. Hijacking of its immunosuppressive functions, as recurrently observed in multiple cancers, facilitates immune evasion and promotes tumor development. Based on these observations, researchers have focused on characterizing indoleamine 2,3-dioxygenase (IDO1), the main enzyme catalyzing the first and limiting step of the pathway, and on developing therapies targeting it. Unfortunately, clinical trials studying IDO1 inhibitors have thus far not met expectations, highlighting the need to unravel this complex signaling pathway further. Recent advances demonstrate that these metabolites additionally promote tumor growth, metastatic dissemination and chemoresistance by a combination of paracrine and autocrine effects. Production of NAD(+) also contributes to cancer progression by providing cancer cells with enhanced plasticity, invasive properties and chemoresistance. A comprehensive survey of this complexity is challenging but necessary to achieve medical success.