Tryptophan Metabolism Contributes to Radiation-Induced Immune Checkpoint Reactivation in Glioblastoma

Purpose:
Immune checkpoint inhibitors have become powerful anticancer agents by reversing tumor-induced immunosuppression. Tryptophan metabolism functions as an immune checkpoint, with the rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) being a key therapeutic target under clinical investigation. This study explores tryptophan metabolism in glioblastoma and evaluates the efficacy of the IDO1 inhibitor GDC-0919, both as monotherapy and in combination with radiation therapy (RT).

Experimental Design:
Metabolomic and transcriptomic analyses were conducted using LC/GC-MS and gene expression profiling on patient-derived glioma samples. Immunocompetent mice were orthotopically implanted with genetically engineered murine glioma cells and treated with GDC-0919, RT, or a combination of both. Tumor-infiltrating immune cells were analyzed via flow cytometry to assess immune modulation.

Results:
Integrated metabolomic and gene expression data identified dysregulated tryptophan metabolism as a hallmark of mesenchymal and classical glioblastoma subtypes. GDC-0919 effectively inhibited this metabolic pathway and penetrated the blood-brain barrier. While GDC-0919 alone did not exhibit direct antitumor effects, it significantly enhanced the therapeutic efficacy of RT, particularly with hypofractionated dosing. RT promoted immune activation, evidenced by increased cytotoxic T-cell infiltration, but also induced immunosuppressive feedback, including upregulation of IDO1 and expansion of regulatory T cells (Tregs). GDC-0919 counteracted this immunosuppression by reducing RT-induced Tregs and further boosting T-cell activation.

Conclusions:
Tryptophan metabolism is a critical metabolic and immunosuppressive node in glioblastoma. Combining RT with IDO1 inhibition via GDC-0919 amplifies antitumor immune responses and may overcome radiation-induced immunosuppression,Navoximod offering a promising therapeutic strategy.