Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis. Cancer cells have distinct metabolic needs compared to normal cells, and identifying these can reveal vulnerabilities for targeted therapies. This study shows that MYC-driven liver tumors rely on increased tryptophan (Trp) uptake but reduce its metabolism in the kynurenine (Kyn) pathway. A no-Trp diet prevents tumor growth and restores normal liver gene expression. Despite Trp starvation, protein synthesis remains unaffected in liver cancer cells. The study identifies indole 3-pyruvate (I3P) as a key metabolite driving liver tumor growth. I3P supplementation restores growth of Trp-starved liver cancer cells, suggesting it as a potential therapeutic target in MYC-driven cancers. Trp is an essential amino acid involved in protein synthesis, serotonin production, and Kyn pathway metabolism. The Kyn pathway involves enzymes like IDO1, IDO2, and TDO2, producing intermediates that can be further metabolized into various compounds. Previous studies show that Trp deprivation can limit cancer growth by altering metabolic pathways. However, the role of Trp and its metabolites in tumor growth is complex and tissue-specific. Trp is also converted into I3P via the activity of IL4I1. I3P acts as a ligand for the AHR transcription factor, promoting cell growth. The study demonstrates that liver tumors driven by MYC exhibit increased Trp uptake and I3P production, which supports tumor growth. Trp starvation reduces I3P levels, leading to tumor growth inhibition. However, protein synthesis remains unaffected, indicating that I3P is a critical driver of tumor growth. The study shows that Trp deprivation reduces the growth of MYC-driven liver tumors and restores normal liver gene expression. Trp starvation also reduces tumor burden without causing permanent damage. I3P supplementation rescues the growth of Trp-starved liver cancer cells in vitro and in vivo, indicating its potential as a therapeutic target. The study also shows that I3P is a ligand for AHR, promoting its nuclear translocation and activating downstream genes involved in cell growth. However, I3P does not affect MYC levels or localization, suggesting that its growth-promoting effects are independent of MYC activation. The findings highlight the importance of I3P in liver tumor biology and suggest that targeting this metabolite could be a promising approach for liver cancer treatment.Tryptophan fuels MYC-dependent liver tumorigenesis through indole 3-pyruvate synthesis. Cancer cells have distinct metabolic needs compared to normal cells, and identifying these can reveal vulnerabilities for targeted therapies. This study shows that MYC-driven liver tumors rely on increased tryptophan (Trp) uptake but reduce its metabolism in the kynurenine (Kyn) pathway. A no-Trp diet prevents tumor growth and restores normal liver gene expression. Despite Trp starvation, protein synthesis remains unaffected in liver cancer cells. The study identifies indole 3-pyruvate (I3P) as a key metabolite driving liver tumor growth. I3P supplementation restores growth of Trp-starved liver cancer cells, suggesting it as a potential therapeutic target in MYC-driven cancers. Trp is an essential amino acid involved in protein synthesis, serotonin production, and Kyn pathway metabolism. The Kyn pathway involves enzymes like IDO1, IDO2, and TDO2, producing intermediates that can be further metabolized into various compounds. Previous studies show that Trp deprivation can limit cancer growth by altering metabolic pathways. However, the role of Trp and its metabolites in tumor growth is complex and tissue-specific. Trp is also converted into I3P via the activity of IL4I1. I3P acts as a ligand for the AHR transcription factor, promoting cell growth. The study demonstrates that liver tumors driven by MYC exhibit increased Trp uptake and I3P production, which supports tumor growth. Trp starvation reduces I3P levels, leading to tumor growth inhibition. However, protein synthesis remains unaffected, indicating that I3P is a critical driver of tumor growth. The study shows that Trp deprivation reduces the growth of MYC-driven liver tumors and restores normal liver gene expression. Trp starvation also reduces tumor burden without causing permanent damage. I3P supplementation rescues the growth of Trp-starved liver cancer cells in vitro and in vivo, indicating its potential as a therapeutic target. The study also shows that I3P is a ligand for AHR, promoting its nuclear translocation and activating downstream genes involved in cell growth. However, I3P does not affect MYC levels or localization, suggesting that its growth-promoting effects are independent of MYC activation. The findings highlight the importance of I3P in liver tumor biology and suggest that targeting this metabolite could be a promising approach for liver cancer treatment.