Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma

Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify 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 through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We further demonstrate that methionine intervention triggers programmed death-ligand 1 (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. • Single-cell atlas of MTAP-del osteosarcoma subtype reveals CD8A + T cell deficiency in TME • Methionine restriction combined with ICT enhances CD8A + T cell infiltration • MAT2A inhibitor improves ICT efficacy through stimulation of PD-L1 expression Mu et al. present a high-resolution single-cell atlas of MTAP-deleted osteosarcoma, revealing deficiency in CD8A + T cells. Methionine restriction or MAT2A inhibitor SCR6639 increases CD8A + T cell infiltration in the tumor microenvironment, enhancing the efficacy of immune checkpoint therapy in MTAP-deleted osteosarcoma.