The Double-Edged Sword: How Neutrophil Traps Can Both Help and Hinder Cancer's Spread

In the intricate battlefield of the human body, the immune system’s foot soldiers, neutrophils, have long been recognized for their heroic role in fighting off infections. But what if these same soldiers, in their attempt to protect, inadvertently create pathways for an even greater enemy to advance? Recent research has uncovered a fascinating and complex story about neutrophil extracellular traps (NETs)—web-like structures neutrophils release to ensnare pathogens—and their paradoxical role in cancer metastasis. While these traps can sometimes help the immune system fight tumors, studies are revealing that NETs can also create a fertile ground for cancer to spread, a discovery that is reshaping our understanding of the tumor microenvironment.

Introduction

For years, the fight against cancer has focused on targeting tumor cells directly. However, scientists are increasingly looking at the tumor microenvironment—the complex ecosystem of cells, blood vessels, and molecules that surrounds a tumor—as a key player in cancer progression. Within this environment, neutrophils are one of the most abundant immune cell types. Their ability to form NETs is a powerful defense mechanism, but this process can be a double-edged sword. A growing body of evidence, including a 2025 review in Theranostics, highlights the bidirectional relationship where cancer cells can induce NET formation, and NETs, in turn, can facilitate cancer progression. Understanding this complex interplay is critical for developing more effective cancer therapies.

Study Summary

To unravel the complex role of NETs in cancer, researchers have employed a range of advanced techniques, from sophisticated mouse models to analyses of human tumor samples. These studies have painted a detailed picture of how these sticky DNA webs influence nearly every step of the metastatic cascade. A pivotal 2025 study in Cancer Cell by Lee et al. revealed how NETs can establish a pre-metastatic niche in the omentum, a fatty tissue in the abdomen, making it more receptive to ovarian cancer cells. This work, along with other recent publications, has illuminated the specific molecular conversations between NETs and cancer cells, opening up new possibilities for therapeutic intervention.

Key Findings

The recent wave of research has yielded several critical insights into the multifaceted role of NETs in cancer metastasis:

• Finding 1: NETs Prepare Distant Sites for Metastasis. Before cancer cells even arrive, NETs can act as advance scouts, preparing the soil in distant organs for tumor seeding. The study by Lee et al. showed that NETs recruit immune-suppressive B cells that produce IL-10, creating a welcoming environment for cancer cells. This finding highlights how NETs can remodel the immune landscape of distant organs to favor metastasis.
• Finding 2: NETs Can Awaken Dormant Cancer Cells. One of the most dangerous aspects of cancer is its ability to lie dormant for years before reawakening and causing a relapse. A groundbreaking 2025 study in Cancer Cell by He et al. discovered that chemotherapy, while killing the main tumor, can induce NET formation in the lungs. These chemotherapy-induced NETs can awaken dormant cancer cells, leading to metastatic outgrowth. This suggests a potential downside to some conventional cancer treatments.
• Finding 3: NETs Promote a More Aggressive Cancer Cell Phenotype. NETs don’t just help cancer cells travel; they can also make them more aggressive. Research has shown that NETs can induce a process called epithelial-mesenchymal transition (EMT), where cancer cells lose their epithelial characteristics and gain migratory and invasive properties. A 2020 study by Martins-Cardoso et al. demonstrated that NETs drive a pro-metastatic phenotype in breast cancer cells by activating the EMT program.
• Finding 4: The Protective Side of NETs. In a fascinating twist, not all NETs are pro-cancer. A 2025 study in the Journal for ImmunoTherapy of Cancer by Liu et al. found that in certain contexts, NETs can actually impede cancer metastatic seeding. They discovered that NET-derived elastase can promote the ability of macrophages to engulf and destroy cancer cells by downregulating the “don’t eat me” signal CD24 on tumor cells. This highlights the dual nature of NETs and the importance of context.

Biological Mechanisms

To understand why these findings matter mechanistically, we need to look at the molecular level. NETs are not just simple traps; they are complex structures loaded with bioactive molecules that can hijack cellular signaling pathways. The study by Martins-Cardoso et al. revealed that when breast cancer cells are exposed to NETs, they undergo a dramatic transformation. The researchers observed a decrease in E-cadherin, a protein that helps epithelial cells stick together, and an increase in N-cadherin and fibronectin, proteins associated with a more migratory, mesenchymal state. This switch is a hallmark of EMT, a key process in metastasis, and shows how NETs can directly reprogram cancer cells to become more invasive.

Molecular Pathways

Diving deeper, the formation of the pre-metastatic niche is orchestrated by a precise series of molecular events. The work by Lee et al. identified the chemoattractant CXCL13 as a key molecule induced by NETs in the omentum. This signal attracts a specific population of innate-like B cells, which are then stimulated by NETs to produce the immunosuppressive cytokine IL-10. This intricate pathway demonstrates how NETs can manipulate immune cell crosstalk to create a pro-tumor environment. Conversely, the protective effects of NETs also have a clear mechanistic basis. Liu et al. found that neutrophil elastase, an enzyme embedded within NETs, can inactivate the PAR2 receptor on cancer cells. This inactivation leads to the downregulation of the CD24 phagocytic checkpoint, essentially removing the cancer cell's "don't eat me" signal and allowing macrophages to clear them more effectively. This finding underscores the context-dependent and complex nature of NETs in cancer.

Relevance to Human Health

Beyond the molecular picture, the implications for human health are substantial. The discovery that chemotherapy can awaken dormant cancer cells by inducing NETs is a sobering reminder of the unintended consequences of some of our most powerful cancer treatments. The study by He et al. not only revealed this dangerous side effect but also offered a potential solution: combining chemotherapy with senolytic drugs (which clear senescent cells) to prevent the formation of these metastasis-promoting NETs. This could lead to new therapeutic strategies that make chemotherapy safer and more effective.

Therapeutic Applications

The growing understanding of NETs in cancer is paving the way for novel therapeutic approaches. As summarized in a comprehensive 2025 review by Wang et al., several strategies are being explored:

• Targeting NET Formation: Drugs that inhibit the key enzymes involved in NETosis, such as PAD4 or MPO, are being investigated as a way to prevent the pro-metastatic effects of NETs.
• Degrading Existing NETs: Using DNases, enzymes that can break down the DNA backbone of NETs, is another promising strategy to dismantle these structures and disrupt their influence on the tumor microenvironment.
• Modulating Neutrophil Activity: Rather than blocking NETs entirely, another approach is to modulate neutrophil function to tip the balance towards their anti-tumor activities, an area of intense investigation as researchers learn more about the dual roles neutrophils play in cancer biology.

Future Directions

Despite these incredible advances, key questions remain. Scientists are now focused on understanding the precise signals that determine whether NETs will play a pro-tumor or anti-tumor role. Future research will likely focus on developing more targeted therapies that can selectively inhibit the harmful effects of NETs while preserving their beneficial, pathogen-fighting functions. As highlighted in a 2025 review in Clinical and Translational Medicine, researchers are actively exploring new NETs-based tumor biomarkers and therapeutic strategies, which could lead to personalized treatments that are tailored to the specific tumor microenvironment of each patient. The coming years promise to be a period of exciting discovery as we continue to unravel the secrets of these fascinating immune structures.

Conclusion

The story of neutrophil extracellular traps in cancer is a compelling example of the beautiful complexity of the immune system. What was once seen as a simple defense mechanism is now understood to be a key regulator of cancer progression, capable of both promoting and suppressing metastasis. This research not only deepens our understanding of cancer biology but also opens up a new frontier of therapeutic possibilities. By learning to tame this double-edged sword, we may be able to develop smarter, more effective treatments that can outmaneuver cancer and improve patient outcomes. The journey is far from over, but the path forward is illuminated by the fascinating and intricate dance between our immune system and the diseases it fights.

References

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3. Liu Y, Ma J, Ma Y, et al. (2025). Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24. J Immunother Cancer. 13(2):e010813. PMID: 40010762
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6. Martins-Cardoso K, Almeida VH, Bagri KM, et al. (2020). Neutrophil Extracellular Traps (NETs) Promote Pro-Metastatic Phenotype in Human Breast Cancer Cells through Epithelial-Mesenchymal Transition. Cancers (Basel). 12(6):1542. PMID: 32545405
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