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The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation

Man Shang1, Huijie Yang1, Ran Yang1

  • 1Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, The province and ministry co-sponsored collaborative innovation center for medical epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

Nature Communications
|March 30, 2021
PubMed

Insights

Tumor metabolic reprogramming aids immune evasion. The enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) enhances tumor resistance to T cells by boosting PD-L1 expression through O-GlcNAcylation.

Area of Science:

  • Cancer Biology
  • Immunology
  • Metabolism

Background:

  • Metabolic enzymes have non-metabolic roles in immune signaling.
  • Tumor metabolic reprogramming's role in immune resistance is not fully understood.

Purpose of the Study:

  • To identify metabolic genes that confer tumor resistance to T cell-mediated killing.
  • To elucidate the mechanism by which tumor metabolism influences immune evasion.

Main Methods:

  • Functional screening of metabolic genes for resistance to T cell cytotoxicity.
  • Investigating the role of MTHFD2 in PD-L1 expression and tumor growth.
  • Analyzing the AKT-mTORC1 pathway and folate cycle metabolites.
  • Assessing protein O-GlcNAcylation and cMYC stability.
  • Correlating MTHFD2 and PD-L1 levels with patient data.

Main Results:

  • Identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) as a key enzyme conferring tumor resistance.
  • MTHFD2 promotes PD-L1 expression, essential for tumor growth.
  • IFN-γ stimulates MTHFD2 via the AKT-mTORC1 pathway.
  • MTHFD2 sustains uridine metabolites, increasing O-GlcNAcylation and cMYC stability, thus upregulating PD-L1.
  • MTHFD2 and PD-L1 levels correlate positively in pancreatic cancer patients.

Conclusions:

  • MTHFD2 plays a critical non-metabolic role in cancer immune evasion.
  • MTHFD2 links tumor metabolism to immune suppression via PD-L1.
  • Targeting MTHFD2 may offer a strategy to overcome tumor immune resistance.

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