Kynurenine pathway impact on immune evasion and inflammation in acute myeloid leukemia

Acute myeloid leukemia (AML) involves immune dysregulation and evasion, in which tryptophan catabolism via the kynurenine pathway (KP) is central. Leukemic blasts often overexpress indoleamine 2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), driving excess L-kynurenine (Kyn) production. Kyn activates the aryl hydrocarbon receptor (AhR), inducing interleukin-6 (IL-6) secretion and STAT3 phosphorylation with NF-κB co-activation, sustaining chronic inflammation. Concomitantly, KP activation is immunosuppressive: Kyn biases T cells toward FoxP3+ regulatory phenotypes, drives exhaustion of T and NK cells, and impairs dendritic and B-cell function, yielding an immunosuppressive milieu rich in IL-10 and IL-35. Together, these actions link chronic inflammation to immune tolerance in AML. By contrast, while upstream enzymes (IDO1/TDO2) are well studied, downstream KP metabolites remain poorly characterized in AML. In other systems, kynurenic acid (KYNA) mediates anti-inflammatory GPR35/AhR signaling, whereas 3-hydroxykynurenine (3−HK) and quinolinic acid (QUIN) generate reactive oxygen species, activate NF-κB–dependent cytokine cascades, and induce T-cell apoptosis. Collectively, the extended KP emerges as a nexus linking inflammatory signaling and immunosuppression in AML, with implications for disease progression, immune escape, and resistance, warranting further investigation.