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<sup>+</sup> 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.
Authors
- Yu Lv (ORCID: https://orcid.org/0009-0000-9289-9559)
- Qí Zhāng (ORCID: https://orcid.org/0000-0001-6300-6491)
- Zhuoying Wang (ORCID: https://orcid.org/0000-0002-8121-5286)
- Jing Xu (ORCID: https://orcid.org/0000-0003-1595-2138)
- Jinzeng Wang (ORCID: https://orcid.org/0009-0000-9267-3525)
- Huanliang Meng
- Renhong Tang
- Haoran Mu (ORCID: https://orcid.org/0000-0003-4763-1363)
- Yafei Jiang (ORCID: https://orcid.org/0000-0001-7272-8453)
- Haiyan Hu (ORCID: https://orcid.org/0000-0002-4373-0383)
- Yingqi Hua
- Yining Tao (ORCID: https://orcid.org/0009-0008-4901-3060)
- Zhengdong Cai
- Zhen Li (ORCID: https://orcid.org/0000-0002-2597-8932)
- Tao Zhang (ORCID: https://orcid.org/0000-0001-9331-8832)
- Yang Liu (ORCID: https://orcid.org/0000-0003-4559-5119)
- Xin He (ORCID: https://orcid.org/0000-0002-5189-7204)
- Hongsheng Wang (ORCID: https://orcid.org/0000-0002-0054-4820)
- Weisong Zhao (ORCID: https://orcid.org/0000-0001-5884-874X)
- Mengkai Yang
- Jun Lin (ORCID: https://orcid.org/0000-0002-4553-4538)
- Feng Tang (ORCID: https://orcid.org/0000-0003-0870-8890)
- Jiakang Shen (ORCID: https://orcid.org/0000-0002-6083-8599)
- Yuqin Yang (ORCID: https://orcid.org/0000-0002-5086-8858)
- Mengxiong Sun (ORCID: https://orcid.org/0000-0002-5514-7160)
- Dongqing Zuo (ORCID: https://orcid.org/0000-0002-6684-9467)
- Wei Sun (ORCID: https://orcid.org/0000-0002-5310-5661)
- Jing Han (ORCID: https://orcid.org/0000-0003-0048-2241)
Institutions
- Shanghai Jiao Tong University (CN)
- Ruijin Hospital (CN)
- Shanghai Chest Hospital (CN)
- Simcere Pharmaceutical (China) (CN)
- Shanghai Cancer Institute (CN)
- Shanghai First People's Hospital (CN)
- Shanghai Sixth People's Hospital (CN)
- Shanghai Institute of Hematology (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-20
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101977
- Citations
- 14
- Primary Topic
- Cancer Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 17.26
Funders
- National Natural Science Foundation of China