Methionine intervention induces PD-L1 expression to enhance the immune checkpoint therapy response in MTAP-deleted osteosarcoma
Haoran Mu, Qí Zhāng, Dongqing Zuo, Jinzeng Wang, Yining Tao, Zhen Li, Xin He, Huanliang Meng, Hongsheng Wang, Jiakang Shen, Mengxiong Sun, Yafei Jiang, Weisong Zhao, Jing Han, Mengkai Yang, Zhuoying Wang, Yu Lv, Yuqin Yang, Jing Xu, Tao Zhang, Yang Liu, Jun Lin, Feng Tang, Renhong Tang, Haiyan Hu, Zhengdong Cai, Wei Sun, Yingqi Hua
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 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.