Atanasov, A. G. et al. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Stine, Z. E., Schug, Z. T., Salvino, J. M. & Dang, C. V. Targeting cancer metabolism in the era of precision oncology. Nat. Rev. Drug Discov. 21, 141–162 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

Article  CAS  PubMed  Google Scholar 

Zhu, J. & Thompson, C. B. Metabolic regulation of cell growth and proliferation. Nat. Rev. Mol. Cell Biol. 20, 436–450 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Elia, I. & Haigis, M. C. Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism. Nat. Metab. 3, 21–32 (2021).

Article  PubMed  PubMed Central  Google Scholar 

Martínez-Reyes, I. & Chandel, N. S. Cancer metabolism: looking forward. Nat. Rev. Cancer 21, 669–680 (2021).

Article  PubMed  Google Scholar 

Warburg, O. The metabolism of carcinoma cells 1. J. Cancer Res. 9, 148–163 (1925).

Article  CAS  Google Scholar 

Leone, R. D. & Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20, 516–531 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bantug, G. R., Galluzzi, L., Kroemer, G. & Hess, C. The spectrum of T cell metabolism in health and disease. Nat. Rev. Immunol. 18, 19–34 (2018).

Article  CAS  PubMed  Google Scholar 

Ganjoo, S. et al. The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy. Front. Immunol. 14, 1172931 (2023).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vijayan, D., Young, A., Teng, M. W. L. & Smyth, M. J. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17, 709–724 (2017).

Article  CAS  PubMed  Google Scholar 

Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35, 1304–1326 (2023).

Article  CAS  PubMed  Google Scholar 

Alves Costa Silva, C. et al. Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial. Nat. Commun. 15, 1633 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. & Muller, A. J. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795–6811 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Meireson, A., Devos, M. & Brochez, L. IDO expression in cancer: different compartment, different functionality? Front. Immunol. 11, 531491 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mellor, A. L. & Munn, D. H. Ido expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

Article  CAS  PubMed  Google Scholar 

Wang, S., Wu, J., Shen, H. & Wang, J. The prognostic value of IDO expression in solid tumors: a systematic review and meta-analysis. BMC Cancer 20, 471 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hezaveh, K. et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55, 324–340.e8 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Campesato, L. F. et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-kynurenine. Nat. Commun. 11, 4011 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

Article  CAS  PubMed  Google Scholar 

Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

Article  CAS  PubMed  Google Scholar 

Schramme, F. et al. Inhibition of tryptophan-dioxygenase activity increases the antitumor efficacy of immune checkpoint inhibitors. Cancer Immunol. Res. 8, 32–45 (2020).

Article  CAS  PubMed  Google Scholar 

Liu, Y. et al. Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation. Cancer Cell 33, 480–494.e7 (2018).

Article  CAS  PubMed  Google Scholar 

Liu, Y. et al. IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor. Nat. Immunol. 22, 358–369 (2021).

Article  CAS  PubMed  Google Scholar 

Monjazeb, A. M. et al. Blocking indolamine-2,3-dioxygenase rebound immune suppression boosts antitumor effects of radio-immunotherapy in murine models and spontaneous canine malignancies. Clin. Cancer Res. 22, 4328–4340 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hou, D. Y. et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 67, 792–801 (2007).

Article  CAS  PubMed  Google Scholar 

Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E. & Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat. Med. 11, 312–319 (2005).

Article  CAS  PubMed  Google Scholar 

Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mitchell, T. C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36, 3223–3230 (2018).

Article  CAS  PubMed  PubMed Central