Targeting the kynurenine pathway in gliomas: Insights into pathogenesis, therapeutic targets, and clinical advances

Gliomas, the most prevalent primary brain tumors, continue to present significant challenges in oncology due to poor patient prognosis despite advances in treatment such as immunotherapy and cancer vaccines. Recent research highlights the potential of targeting tryptophan metabolism, particularly the kynurenine pathway (KP) and combinatorial approaches with immunotherapies, as a promising strategy in cancer research. The key enzymes of the kynurenine pathway, such as IDO1, IDO2, and TDO, and metabolites like kynurenine, kynurenic acid, and quinolinic acid, are implicated in fostering an immunosuppressive tumor microenvironment and promoting glioma cell survival. In glioblastoma, a highly aggressive glioma subtype, elevated IDO and TDO expression correlates with reduced survival rates. KP metabolites, such as kynurenine (KYN), 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA), and quinolinic acid (QUIN), are involved in modulating immune responses, oxidative stress, neuroprotection, and neurotoxicity. This review synthesizes recent findings on the kynurenine pathway involvement in glioma pathogenesis, examining potential therapeutic targets within this pathway and discussing ongoing clinical trials that draw attention to treatments based on this pathway. Furthermore, it highlights novel findings on the post-translational modifications of kynurenine pathway enzymes and their regulatory roles, presenting their potential as therapeutic targets in gliomas.