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NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity

Janna Heide1, Agnes J Bilecz1, Samarjit Patnaik2

  • 1Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.

Nature
|July 23, 2025
PubMed

Insights

Nicotinamide N-methyltransferase (NNMT) fuels cancer by recruiting immunosuppressive cells. Inhibiting NNMT in cancer-associated fibroblasts (CAFs) boosts anti-tumor immunity and reduces tumor growth, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Cancer-associated fibroblasts (CAFs) play a critical role in tumor progression.
  • Targeting CAFs remains a challenge in cancer therapy.

Purpose of the Study:

  • To investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer.
  • To identify NNMT as a potential therapeutic target for cancer treatment.

Main Methods:

  • Spatial transcriptomics and single-cell RNA sequencing were employed.
  • NNMT's role was assessed in syngeneic mouse models of ovarian, breast, and colon cancer.
  • High-throughput screening was used to identify NNMT inhibitors.

Main Results:

  • NNMT promotes tumor growth by inducing H3K27me3 hypomethylation in CAFs, leading to the secretion of immunosuppressive factors and recruitment of myeloid-derived suppressor cells (MDSCs).
  • NNMT knockout impaired tumor growth and enhanced CD8+ T cell activation in multiple cancer models.
  • A novel NNMT inhibitor reduced tumor burden, metastasis, and restored anti-tumor immunity.

Conclusions:

  • NNMT is a key regulator of CAFs and immunosuppression within the tumor microenvironment.
  • Targeting NNMT represents a promising therapeutic strategy to enhance anti-tumor immunity and overcome treatment resistance.

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