Targeting the tumor microenvironment offers new hope for overcoming treatment resistance
Ovarian cancer has long been one of the most formidable opponents in women's health. Dubbed a "silent killer," it often progresses unnoticed until reaching advanced stages, leaving patients with limited treatment options and dwindling hope.
For decades, the standard approach has involved radical surgery followed by chemotherapy. While initially effective for many patients, the disease often returns with a vengeance. "Over 80% of newly diagnosed patients achieve partial or complete remission after initial treatment; however, most experience relapse within three years," notes a recent comprehensive review .
This pattern of recurrence, coupled with developing resistance to chemotherapy, has created an urgent need for innovative treatment strategies that go beyond traditional approaches.
The medical community has responded with targeted therapies that represent a paradigm shift in ovarian cancer treatment. Among the most promising recent developments is an approach that doesn't attack cancer cells directly but instead dismantles their support system—a strategy that could finally turn the tide against this devastating disease.
To understand the breakthrough in ovarian cancer treatment, we must first look at where tumors live. Cancer cells don't exist in isolation; they inhabit a complex ecosystem known as the tumor microenvironment. This environment includes various cell types, signaling molecules, and structural components that collectively influence cancer growth and treatment response.
One key player in this microenvironment is the cancer-associated fibroblast (CAF). Unlike normal fibroblasts that maintain tissue structure and facilitate healing, CAFs have been "corrupted" by the tumor to serve its purposes.
What makes CAFs particularly appealing as therapeutic targets is their stability. "Most therapies focus on the cancer cells, but we are interested in the fibroblasts in the surrounding stroma," says Lengyel. "These cells don't mutate like cancer cells, which makes them more stable and, we think, more targetable" 9 .
This insight—that we might defeat cancer not by direct assault but by undermining its support network—represents a fundamental shift in therapeutic strategy that could have implications far beyond ovarian cancer.
The groundbreaking discovery came when researchers identified a specific enzyme called nicotinamide N-methyl transferase (NNMT) as a key driver in the transformation of normal fibroblasts into tumor-promoting CAFs. In a landmark 2019 study published in Nature, Lengyel's team demonstrated that NNMT, a metabolic enzyme, is highly expressed in CAFs and converts normal fibroblasts into tumor-promoting fibroblasts by changing their epigenetic and metabolic programming 9 .
This discovery was significant because it identified not just a biomarker but an active driver of the tumor-promoting environment. "The enzyme NNMT induces widespread epigenetic changes in fibroblasts that promote tumor growth," notes Dr. Janna Heide, a postdoctoral researcher in the Lengyel Lab and first author of the study. "Inhibiting NNMT has the potential to reverse these changes and reduce the tumor-supportive role of fibroblasts" 9 .
Researchers discover NNMT is highly expressed in cancer-associated fibroblasts (CAFs) in ovarian cancer.
NNMT found to reprogram fibroblasts through epigenetic changes, creating a tumor-supportive environment.
NNMT-expressing CAFs shown to convert monocytes into immunosuppressive cells that protect tumors.
The team's most recent Nature study, published in 2025, revealed exactly how NNMT promotes immune evasion. They discovered that NNMT-expressing CAFs secrete proteins that convert monocytes (a type of white blood cell) into myeloid-derived suppressor cells (MDSCs)—cells that actively suppress the immune system's ability to recognize and destroy cancer cells 9 .
This double whammy—simultaneously creating a tumor-friendly environment while disarming the body's natural defenses—explains why ovarian cancer has been so difficult to treat effectively. But it also presented a golden opportunity: if researchers could block NNMT, they might be able to reverse both processes simultaneously.
To translate their discovery into a potential treatment, the University of Chicago team collaborated with scientists at the National Center for Advancing Translational Sciences (NCATS) and the National Cancer Institute (NCI) Experimental Therapeutics (NExT) program. Together, they embarked on an extensive drug screening process, testing over 150,000 compounds to identify potential NNMT inhibitors 9 .
The experimental results offered compelling evidence for the potential of NNMT inhibition as a therapeutic strategy. The table below summarizes key findings from the preclinical studies:
| Treatment Approach | Effect on Tumor Burden | Impact on Immune Activity | Overall Efficacy |
|---|---|---|---|
| NNMT inhibitor alone | Decreased | Restored immune activity | Significant reduction |
| Immunotherapy alone | Minimal change | Limited improvement | Poor |
| NNMT inhibitor + immunotherapy | Haltered tumor growth | Synergistic immune restoration | Remarkable control |
"Immunotherapy hasn't worked in ovarian cancer, but the combination therapy of an NNMT inhibitor with immunotherapy worked remarkably well in our preclinical models. It was exciting to show that tumor growth can be controlled without even touching the cancer cells, just by reprogramming the supporting cells around them" - Dr. Ernst Lengyel 9 .
NNMT is expressed in fibroblasts, which don't mutate rapidly like cancer cells, reducing likelihood of treatment resistance.
Reverses the immunosuppressive environment created by CAFs, enabling body's natural defenses to fight cancer.
Works effectively with existing immunotherapies, enhancing efficacy of multiple treatment approaches.
NNMT is highly expressed in high-grade serous ovarian cancer, potentially benefiting the majority of patients.
Advancements in ovarian cancer research depend on sophisticated laboratory tools and techniques. The table below highlights key resources that enable discoveries like the NNMT inhibitor:
| Research Tool | Function | Application in Ovarian Cancer Research |
|---|---|---|
| Cell lines | Laboratory-grown cancer cells | Study cancer biology and test drug responses 8 |
| Patient-derived organoids | Miniature 3D tumor models grown from patient samples | More accurate representation of human tumors than traditional cell lines |
| Genetically engineered mouse models | Animals designed to develop ovarian cancer | Study disease progression and treatment in living organisms |
| Spatial transcriptomics | Detects gene expression while preserving tissue structure | Reveals cellular interactions within tumor microenvironment 1 |
| Circulating tumor DNA (ctDNA) assays | Detects tumor DNA fragments in blood | Monitors treatment response and detects recurrence |
The discovery of NNMT's role in ovarian cancer and the development of a targeted inhibitor represents a significant milestone in the field. It demonstrates the power of looking beyond cancer cells themselves to the entire ecosystem that supports their growth.
This approach is part of a broader shift in ovarian cancer treatment that includes other targeted therapies such as PARP inhibitors for women with BRCA mutations and anti-angiogenic agents like bevacizumab that block tumor blood supply 2 6 . What makes the NNMT strategy particularly promising is its potential applicability to the most common and deadly form of ovarian cancer—high-grade serous ovarian cancer—which has historically had limited treatment options.
Next steps involve moving NNMT inhibitors into clinical trials to evaluate safety and efficacy in human patients.
Additional studies needed to understand NNMT's role in other cancer types and potential combination therapies.
While more research is needed before NNMT inhibitors become available to patients, the findings offer new hope for transforming ovarian cancer from a deadly disease to a manageable condition. As research continues, the prospect of effectively controlling advanced ovarian cancer appears increasingly within reach—a development that would mean more women can experience the joy of remission and continue advocating for cancer research 1 .
The fight against ovarian cancer is far from over, but with innovative approaches that target both the cancer and its environment, researchers are building a more hopeful future—one discovery at a time.