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The aryl hydrocarbon receptor (AHR) pathway modulates the immune system in response to kynurenine, an endogenous tryptophan metabolite. IDO1 and TDO2 catalyze kynurenine production, which promotes cancer progression by compromising host immunosurveillance. However, it is unclear whether the AHR activation regulates the malignant traits of cancer such as metastatic capability or cancer stemness. Here, we carried out systematic analyses of metabolites in patient‐derived colorectal cancer spheroids and identified high levels of kynurenine and  TDO2  that were positively associated with liver metastasis. In a mouse colon cancer model, TDO2 expression substantially enhanced liver metastasis, induced AHR‐mediated  PD‐L1  transactivation, and dampened immune responses; these changes were all abolished by  PD‐L1  knockout. In patient‐derived cancer spheroids, TDO2 or AHR activity was required for not only the expression of  PD‐L1 , but also for cancer stem cell (CSC)‐related characteristics and Wnt signaling.  TDO2  was coexpressed with both  PD‐L1  and nuclear β‐catenin in colon xenograft tumors, and the coexpression of  TDO2  and  PD‐L1  was observed in clinical colon cancer specimens. Thus, our data indicate that the activation of the TDO2‐kynurenine‐AHR pathway facilitates liver metastasis of colon cancer via  PD‐L1 –mediated immune evasion and maintenance of stemness.

Stemness and immune evasion conferred by the TDO2‐AHR pathway are associated with liver metastasis of colon cancer