Immunomodulatory mechanisms driving tumor escape in glioblastoma: The central role of IDO and tryptophan metabolism in local and systemic immunotolerance

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor exhibiting extensive immune evasion mechanisms that hinder effective therapeutic interventions. This narrative review explores the immu- nomodulatory pathways contributing to tumor escape in GBM, specifically focusing on the role of Tryptophan (TRP) metabolism and its downstream mediators Tryptophan metabolism through the kynurenine pathway (KP) is initiated by indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO2) enzymes and serves as a crucial mechanism for promoting an immunosuppressive microenvironments and systemic immunotol- erance. Emerging evidence also indicates a non-enzymatic role for IDO1 signaling in these processes. The downstream effectors interact with immune cells, inducing local immunosuppression within the tumor micro- environment and altering peripheral immune responses. Methods: We systematically reviewed databases (MEDLINE via PubMed, Science Direct, and Embase) through October 2024 to highlight the interplay between local immune escape mechanisms and circulating immuno- tolerance, emphasizing the role of TRP metabolic enzymes in supporting GBM progression. Results: The literature review identified 99 records. TRP-related mechanisms play a central role in fostering immunotolerance in GBM. These phenomena involve intricate interactions between the infiltrating and circu- lating myeloid and lymphoid compartments, ultimately shaping a tolerant, pro-tumoral environment and the peripheral immunophenotype. Conclusions: The biological activity of IDO1 and TRP metabolites positions these compounds as potential markers of disease activity and promising molecular targets for future therapeutic approaches.