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

Haoran Mu; Qi Zhang; 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; Liu Yang; Jun Lin; Feng Tang; Renhong Tang; Haiyan Hu; Zhengdong Cai; Wei Sun; Yingqi Hua

doi:10.1016/j.xcrm.2025.101977

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

Cell Rep Med. 2025 Mar 18;6(3):101977. doi: 10.1016/j.xcrm.2025.101977. Epub 2025 Feb 20.

Authors

Haoran Mu¹, Qi Zhang², Dongqing Zuo¹, Jinzeng Wang³, Yining Tao¹, Zhen Li⁴, Xin He¹, Huanliang Meng¹, Hongsheng Wang¹, Jiakang Shen¹, Mengxiong Sun¹, Yafei Jiang¹, Weisong Zhao¹, Jing Han¹, Mengkai Yang¹, Zhuoying Wang¹, Yu Lv¹, Yuqin Yang⁵, Jing Xu¹, Tao Zhang¹, Liu Yang¹, Jun Lin⁶, Feng Tang⁷, Renhong Tang⁸, Haiyan Hu⁹, Zhengdong Cai¹, Wei Sun¹⁰, Yingqi Hua¹¹

Affiliations

¹ Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.
² Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jz.wang@sjtu.edu.cn.
⁴ State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China.
⁵ Department of Laboratory Animal Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China.
⁸ State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China; Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China; Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China.
⁹ The Drug and Device Phase I Clinical Research Ward/Demonstration Research Ward of Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
¹⁰ Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. Electronic address: viv-sun@sjtu.edu.cn.
¹¹ Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. Electronic address: hua_yingqi@163.com.

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.

Keywords: IKZF1; MAT2A; MTAP deletion; PD-L1; immunotherapy; methionine metabolism; osteosarcoma; tumor microenvironment.

MeSH terms

Animals
B7-H1 Antigen* / genetics
B7-H1 Antigen* / metabolism
Bone Neoplasms* / drug therapy
Bone Neoplasms* / genetics
Bone Neoplasms* / immunology
Bone Neoplasms* / pathology
CD8-Positive T-Lymphocytes / immunology
Cell Line, Tumor
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Methionine Adenosyltransferase / antagonists & inhibitors
Methionine Adenosyltransferase / metabolism
Methionine* / metabolism
Methionine* / pharmacology
Mice
Mice, Inbred C57BL
Osteosarcoma* / drug therapy
Osteosarcoma* / genetics
Osteosarcoma* / immunology
Osteosarcoma* / metabolism
Osteosarcoma* / pathology
Purine-Nucleoside Phosphorylase* / deficiency
Purine-Nucleoside Phosphorylase* / genetics
Purine-Nucleoside Phosphorylase* / metabolism
Tumor Microenvironment / drug effects

Substances

Methionine
Purine-Nucleoside Phosphorylase
B7-H1 Antigen
5'-methylthioadenosine phosphorylase
Immune Checkpoint Inhibitors
CD274 protein, human
Methionine Adenosyltransferase