Gagliardi Filippo, De Domenico Pierfrancesco, Snider Silvia, Roncelli Francesca, Comai Stefano, Mortini Pietro
IRCCS San Raffaele Scientific Institute, Department of Neurosurgery and Gamma Knife Radiosurgery, Milan 20132, Italy.
IRCCS San Raffaele Scientific Institute, Department of Neurosurgery and Gamma Knife Radiosurgery, Milan 20132, Italy.
Crit Rev Oncol Hematol. 2025 May;209:104657. doi: 10.1016/j.critrevonc.2025.104657. Epub 2025 Feb 21.
Glioblastoma (GBM) is the most aggressive primary brain tumor exhibiting extensive immune evasion mechanisms that hinder effective therapeutic interventions. This narrative review explores the immunomodulatory 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 immunotolerance. 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 microenvironment and altering peripheral immune responses.
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 immunotolerance, emphasizing the role of TRP metabolic enzymes in supporting GBM progression.
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 circulating myeloid and lymphoid compartments, ultimately shaping a tolerant, pro-tumoral environment and the peripheral immunophenotype.
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.
胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，具有广泛的免疫逃逸机制，阻碍了有效的治疗干预。本叙述性综述探讨了导致GBM肿瘤逃逸的免疫调节途径，特别关注色氨酸（TRP）代谢及其下游介质的作用。通过犬尿氨酸途径（KP）的色氨酸代谢由吲哚胺2,3-双加氧酶（IDO）和色氨酸-2,3-双加氧酶（TDO2）启动，是促进免疫抑制微环境和全身免疫耐受的关键机制。新出现的证据还表明IDO1信号在这些过程中具有非酶作用。下游效应器与免疫细胞相互作用，在肿瘤微环境中诱导局部免疫抑制，并改变外周免疫反应。
我们系统地检索了截至2024年10月的数据库（通过PubMed、Science Direct和Embase检索MEDLINE），以突出局部免疫逃逸机制与循环免疫耐受之间的相互作用，强调TRP代谢酶在支持GBM进展中的作用。
文献综述共识别出99条记录。TRP相关机制在促进GBM免疫耐受中起核心作用。这些现象涉及浸润和循环的髓系及淋巴系细胞间复杂的相互作用，最终形成一个耐受的、促肿瘤的环境以及外周免疫表型。
IDO1和TRP代谢产物的生物学活性使这些化合物成为疾病活性的潜在标志物以及未来治疗方法有前景的分子靶点。
