IDO1 methylation by EZH2 confers resistance to its targeted therapy in colorectal cancer through tryptophan-kynurenine metabolic rewiring.

In a colorectal cancer mouse model, IDO1 is pinpointed as a key mediator of EZH2 inhibitor resistance, with EZH2 blockade driving tryptophan–kynurenine pathway hyperactivation.

• Why it matters: EZH2-targeted therapy efficacy is limited by metabolic rewiring that enables resistance, but the specific metabolic mediator and its regulation were unclear.
• What they did: An in vivo genome-wide CRISPR loss-of-function screen in CRC mice identified IDO1; EZH2 inhibition increased IDO1 protein and tryptophan–kynurenine flux, and IDO1 blockade suppressed growth and restored drug sensitivity in vitro and in vivo.
• The result: EZH2 directly binds and methylates IDO1, promoting ubiquitination and degradation; inhibiting EZH2 stabilizes IDO1, increases tryptophan–kynurenine metabolism, and thereby confers therapeutic resistance.

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