Methionine Intervention Induces PD-L1 Expression to Enhance the Immune Checkpoint Therapy Response in MTAP-deleted Osteosarcoma

ABSTRACT: Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we have identified a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a 'cold' tumor microenvironment. MTAP-deleted OS relies on methionine metabolism, and is sensitive to methionine intervention, achieved either through dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We have further demonstrated that methionine intervention triggers PD-L1 transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

PROVIDER: MTBLS11985 | MetaboLights | 2026-06-09

REPOSITORIES: MetaboLights