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

Haoran Mu1, Qi Zhang2, Dongqing Zuo1

  • 1Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China.

Cell Reports. Medicine
|February 21, 2025
PubMed

Insights

Osteosarcoma with MTAP deletion resists immune therapy. Methionine intervention, by altering metabolism, enhances immune response and ICT efficacy in preclinical models.

Area of Science:

  • Oncology
  • Immunology
  • Metabolic Research

Background:

  • Osteosarcoma (OS) is a bone cancer with poor outcomes and low response to immune checkpoint therapy (ICT).
  • A subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion shows resistance to ICT, characterized by a "cold" tumor microenvironment.

Purpose of the Study:

  • To investigate the role of MTAP deletion in OS immune evasion.
  • To explore methionine metabolism as a therapeutic target in MTAP-deleted OS.
  • To evaluate the combination of methionine intervention and ICT in preclinical OS models.

Main Methods:

  • Genomics and transcriptomics analyses to identify OS subgroups.
  • In vitro and in vivo models of MTAP-deleted OS.
  • Assessment of methionine metabolism, PD-L1 expression, immune cell infiltration, and survival.

Main Results:

  • MTAP deletion in OS is linked to ICT resistance and a "cold" tumor microenvironment.
  • Methionine metabolism is a critical vulnerability in MTAP-deleted OS.
  • Methionine intervention (dietary restriction or MAT2A inhibition) upregulates PD-L1 via IKZF1.
  • Methionine intervention enhances immune signaling and CD8+ T cell infiltration.
  • Combination therapy significantly improved survival in murine models.

Conclusions:

  • MTAP deletion confers immune resistance in osteosarcoma through metabolic alterations.
  • Targeting methionine metabolism represents a promising strategy to sensitize MTAP-deleted OS to ICT.
  • Combination of methionine intervention and ICT shows significant therapeutic potential for this OS subgroup.
Keywords:
IKZF1MAT2AMTAP deletionPD-L1immunotherapymethionine metabolismosteosarcomatumor microenvironment

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