A positive feedback loop of kynurenine-AhR-EMT upregulates tryptophan metabolic enzymes via epigenetic modification to facilitate immune escape in triple-negative breast cancer.

BACKGROUND

Triple-negative breast cancer (TNBC) is prone to immune escape, and the synergistic mechanism of kynurenine, AhR, and EMT remains unclear.

METHODS

TNBC cell lines and 4T1 orthotopic breast cancer mice were used for molecular, cellular, and in vivo intervention experiments.

RESULTS

Kynurenine induced EMT in an AhR-dependent way, promoted cell migration and invasion, upregulated CCL2/CCL22, and inhibited the function of CD8⁺GrB⁺ T cells. Snail overexpression promotes H3K4me3 histone modification at IDO1 and TDO2 promoters to epigenetically amplify tryptophan metabolic enzyme expression. The AhR antagonist CH-223191 blocked the loop and reversed tumor immune escape.

CONCLUSION

This study demonstrates that the kynurenine-AhR-EMT positive feedback loop drives immune escape in TNBC, providing a rationale for combined targeted therapy.