Introduction
Neutrophils, the most abundant type of white blood cell in the human body, have long been recognized as the immune system’s first line of defense against infection. Traditionally viewed as simple, short-lived phagocytes, our understanding of their role in health and disease has evolved dramatically. In the complex landscape of cancer, neutrophils have emerged as critical and highly versatile players, exhibiting a remarkable duality that can either fuel tumor progression or mount a potent anti-tumor attack. This phenomenon is largely attributed to the polarization of Tumor-Associated Neutrophils (TANs) into distinct phenotypes: the pro-tumor “N2” subtype and the anti-tumor “N1” subtype [1, 2].
This article explores the dual nature of neutrophils in the tumor microenvironment (TME) and delves into the emerging therapeutic strategies designed to manipulate their function. These strategies follow a two-pronged approach: blocking the pro-tumor activities of N2 neutrophils and promoting the anti-tumor capacities of their N1 counterparts. By understanding and targeting these specific mechanisms, researchers hope to unlock a new frontier in cancer immunotherapy.
The Dark Side: Pro-Tumor Activities of Neutrophils
In many cancer types, a high infiltration of neutrophils is associated with poor prognosis. This is because tumor cells can co-opt these immune cells, polarizing them towards an N2 phenotype that actively supports cancer growth, invasion, and metastasis through several key mechanisms.
“Neutrophils exhibit a dual role within the tumor microenvironment, oscillating between pro-tumor and anti-tumor activities that critically influence cancer progression and therapeutic responses.” — Wu et al., 2024 [3]
One of the primary pro-tumor functions is the creation of an immunosuppressive TME. N2 neutrophils can directly inhibit the function of cytotoxic T cells, the primary soldiers of the anti-cancer immune response. This is achieved through mechanisms such as the production of Reactive Oxygen Species (ROS) and the release of enzymes like arginase-1 (Arg-1) [4]. Furthermore, neutrophils can form Neutrophil Extracellular Traps (NETs), web-like structures of DNA and proteins that, while designed to trap pathogens, can paradoxically promote cancer metastasis by creating a favorable niche for circulating tumor cells [5].
Tumors actively recruit these pro-tumor neutrophils from the bloodstream. The CXCLs/CXCR2 signaling axis plays a pivotal role in this process, acting as a chemical beacon that guides neutrophils to the tumor site. Once in the TME, cytokines such as Granulocyte-Colony Stimulating Factor (G-CSF) and Tumor Necrosis Factor-alpha (TNF-α) further promote their survival and reinforce their pro-tumor functions [6].
Blocking Pro-Tumor Activity: A Therapeutic Strategy
Given their detrimental role, a major focus of cancer immunotherapy research is to block the pro-tumor activities of N2 neutrophils. Several strategies, as illustrated in the provided diagram, are under investigation.
| Strategy | Mechanism | Target | Clinical Development |
| A. Targeting Immunosuppressive Cells | Using antibodies to eliminate or inhibit immunosuppressive neutrophils. | CD33 | Preclinical and clinical studies are exploring CD33 as a target for myeloid-derived suppressor cells, including neutrophils, in acute myeloid leukemia (AML) and other cancers [7]. |
| B. Inhibiting Recruitment | Blocking the CXCR2 receptor to prevent neutrophils from migrating to the tumor. | CXCR2 | Several CXCR2 inhibitors (e.g., Navarixin, AZD5069) have entered clinical trials, showing some promise in slowing tumor growth, particularly in combination with other therapies like checkpoint inhibitors [8]. |
| C. Blocking Activation Signals | Neutralizing key cytokines that promote the survival and pro-tumor function of neutrophils. | G-CSF, TNF-α | Anti-TNF-α therapies are established in autoimmune diseases, and their role in cancer is being explored. G-CSF inhibitors are also under investigation to prevent neutrophil-mediated immunosuppression [9]. |
| D. Inhibiting T-Cell Suppression | Preventing neutrophils from suppressing T-cell activity by blocking direct cell contact or ROS production. | Mac-1, ROS | This remains a more preclinical area of research, focusing on identifying specific molecules involved in the neutrophil-T cell interaction. |
These strategies aim to disarm the tumor’s ability to hijack neutrophils for its own benefit, thereby making the TME less hospitable for cancer growth and more accessible for other immune cells.
The Bright Side: Anti-Tumor Capacities of Neutrophils
While the pro-tumor activities of neutrophils have been a major focus of research, it is crucial to recognize their potent anti-cancer capabilities. When polarized to an “N1” phenotype, neutrophils can act as formidable warriors against tumors. This anti-tumor activity is multifaceted, involving direct killing of cancer cells, recruitment and activation of other immune cells, and modulation of the TME to favor an anti-tumor response.
N1 neutrophils can directly kill tumor cells through the release of cytotoxic molecules, including ROS, proteases, and other granular contents. They can also induce apoptosis in cancer cells through the Fas/FasL pathway. Furthermore, N1 neutrophils can act as antigen-presenting cells (APCs), albeit less efficiently than professional APCs like dendritic cells. By presenting tumor antigens to T cells, they can help initiate and amplify the adaptive immune response against the cancer.
Promoting Anti-Tumor Capacities: A Therapeutic Strategy
The second prong of neutrophil-targeted therapy focuses on harnessing and enhancing the natural anti-tumor capabilities of N1 neutrophils. The goal is to shift the balance from a pro-tumor N2-dominated TME to an anti-tumor N1-dominated one. The strategies to achieve this are as follows:
| Strategy | Mechanism | Target | Clinical Development |
| E. Interfering with Inhibitory Checkpoints | Blocking inhibitory receptors on neutrophils to restore their antibody-mediated anti-tumor activities. | Innate immune inhibitory checkpoints | This is an emerging area of research, with a focus on identifying and targeting neutrophil-specific inhibitory receptors that dampen their anti-tumor functions. |
| F. Targeting Downstream Signaling | Inhibiting the downstream signaling pathways of inhibitory receptors to unleash the cytotoxic potential of neutrophils. | Downstream inhibitory proteins | Preclinical studies are investigating the role of various intracellular signaling molecules in regulating neutrophil activity, with the aim of identifying druggable targets. |
| G. Using IgA-Based Therapeutics | Employing IgA-based monoclonal antibodies (mAbs) that bind to the activating FcαRI receptor on neutrophils, triggering potent anti-tumor responses. | FcαRI | IgA-based antibodies have shown promise in preclinical models, demonstrating superior neutrophil-mediated killing of tumor cells compared to IgG-based antibodies [10]. |
| H. Modifying IgG Antibodies | Engineering the Fc region of IgG therapeutic antibodies to increase their affinity for activating Fcγ receptors on neutrophils, thereby enhancing antibody-dependent cell-mediated cytotoxicity (ADCC). | Fcγ receptors | Several next-generation therapeutic antibodies with enhanced Fc receptor binding are in clinical development, aiming to improve their efficacy by better engaging neutrophils and other immune cells. |
The Challenge of Duality: Clinical Implications and Future Directions
The dual role of neutrophils in cancer presents a significant challenge for therapeutic development. A therapy designed to deplete all neutrophils could be detrimental, as it would also eliminate the beneficial anti-tumor N1 population. Therefore, the future of neutrophil-targeted therapy lies in the ability to selectively target the pro-tumor N2 phenotype while preserving or even enhancing the anti-tumor N1 phenotype.
This requires a deeper understanding of the molecular mechanisms that govern neutrophil polarization. The identification of specific markers for N1 and N2 neutrophils is a critical area of ongoing research. Such markers would not only allow for better patient stratification but also enable the development of highly targeted therapies.
Combination therapies are also a promising avenue. For example, combining CXCR2 inhibitors with checkpoint inhibitors like anti-PD-1 antibodies has shown synergistic effects in preclinical models, leading to enhanced tumor regression and improved survival [11]. The idea is to first block the recruitment of pro-tumor neutrophils and then unleash the full potential of the adaptive immune system.
Conclusion
Neutrophils are no longer considered simple foot soldiers of the immune system. Their remarkable plasticity and dual role in cancer have placed them at the forefront of cancer immunology research. The ability to therapeutically manipulate neutrophil function, by either blocking their pro-tumor activities or promoting their anti-tumor capacities, holds immense promise for the future of cancer treatment. As our understanding of neutrophil biology continues to grow, we can expect to see the development of novel and more effective neutrophil-targeted therapies that will hopefully translate into improved outcomes for cancer patients.
References
1.Fridlender, Z. G., Sun, J., Kim, S., Kapoor, V., Cheng, G., Ling, L., … & Albelda, S. M. (2009). Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer cell, 16(3), 183-194. https://www.cell.com/cancer-cell/fulltext/S1535-6108(09)00215-3
2.Koenderman, L., & Vrisekoop, N. (2024). Neutrophils in cancer: from biology to therapy. Cellular & Molecular Immunology, 22(1), 4-23. https://www.nature.com/articles/s41423-024-01244-9
3.Wu, G., et al. (2024). Neutrophils’ dual role in cancer: from tumor progression to therapeutic targets. Journal of Translational Medicine, 22(1), 1-15.
4.Furumaya, C., Martinez-Sanz, P., & Bouti, P. (2020). Plasticity in pro-and anti-tumor activity of neutrophils: shifting the balance. Frontiers in immunology, 11, 2100. https://www.frontiersin.org/articles/10.3389/fimmu.2020.02100/full
5.Masucci, M. T., Minopoli, M., & Carriero, M. V. (2020). The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Frontiers in immunology, 11, 1749. https://www.frontiersin.org/articles/10.3389/fimmu.2020.01749/full
6.Cheng, Y., Mo, F., Li, Q., Han, X., Shi, H., Chen, S., … & Wei, X. (2021). Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin. Molecular Cancer, 20(1), 1-18. https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-021-01355-1
7.Borot, F., et al. (2019). Gene-edited stem cells enable CD33-directed immune therapy against leukemias. Proceedings of the National Academy of Sciences, 116(24), 11978-11987. https://www.pnas.org/doi/10.1073/pnas.1819992116
8.Armstrong, A. J., et al. (2024). CXCR2 antagonist navarixin in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer. Clinical Cancer Research, 30(4), 743-751. https://pubmed.ncbi.nlm.nih.gov/38324085/
9.Ioannis, K., et al. (2021). G-CSF in tumors: aggressiveness, tumor microenvironment, and cancer therapy. Cancers, 13(8), 1843. https://pmc.ncbi.nlm.nih.gov/articles/PMC8044051/
10.Boivin, G., et al. (2021). Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy. OncoImmunology, 10(1), 1876597. https://www.tandfonline.com/doi/full/10.1080/2162402X.2021.1876597
11.Wang, P. F., Zhang, Y. X., Su, J., Yao, K., Li, S. W., Huang, G. R., & Yan, C. X. (2020). Neutrophil depletion enhances the therapeutic effect of PD-1 antibody on glioma. Aging (Albany NY), 12(15), 15290. https://pmc.ncbi.nlm.nih.gov/articles/PMC7467393/