Indoleamine 2,3-dioxygenase-1 involves in CD8+T cell exhaustion in glioblastoma via regulating tryptophan levels.

Indoleamine 2,3-dioxygenase-1 (IDO-1) is an enzyme that catalyzes the metabolism of tryptophan (Trp). It is expressed in limited amounts in normal tissues but significantly upregulated during inflammation and infection. Various inflammatory factors, especially IFN-γ, can induce the expression of IDO-1. While extensive research has been conducted on the role of IDO-1 in tumors, its specific role in complex central nervous system tumors such as glioblastoma (GBM) remains unclear. This study aims to explore the role of IDO-1 in the development of GBM and analyze its association with tryptophan levels and CD8+T cell exhaustion in the tumor region. To achieve this, we constructed an orthotopic mouse glioblastoma tumor model to investigate the specific mechanisms between IDO-1, GBM, and CD8+T cell exhaustion. Our results showed that IDO-1 can promote CD8+T cell exhaustion by reducing tryptophan levels. When IDO-1 was knocked down in glioblastoma cells, other cells within the tumor microenvironment upregulated IDO-1 expression to compensate for the loss and enhance immunosuppressive effects. Therefore, the data suggest that the GBM microenvironment controls tryptophan levels by regulating IDO-1 expression, which plays a critical role in immune suppression. These findings support the use of immune therapy in combination with IDO-1 inhibitors or tryptophan supplementation as a potential treatment strategy.