Neutrophils: hidden accomplices in colorectal cancer?

By Ana Espino | Published on March 23, 2026 | 3 min read


Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. While the role of T lymphocytes in tumor immunosurveillance is well established, the involvement of neutrophils—key cells of innate immunity—is drawing increasing attention.  

Long regarded as simple mediators of acute inflammation, neutrophils are now recognized as complex regulators of the tumor microenvironment. Their accumulation in colorectal tumors is associated with poorer clinical outcomes, although their functions remain heterogeneous and context-dependent.  

This 2025 review analyzes the role of both intratumoral and circulating neutrophils in colorectal carcinogenesis, their molecular mechanisms of action, and their potential as biomarkers and therapeutic targets.  

Inflammation: a hidden driver of progression?  

The authors first describe the recruitment of neutrophils to the tumor, mediated by chemokines such as CXCL1, CXCL2, and IL-8 (CXCL8), which activate the CXCR2 receptor. Once infiltrated, neutrophils can adopt different functional phenotypes.  

Two subtypes are proposed: N1 neutrophils, with antitumor properties that enhance immune cytotoxicity, and N2 neutrophils, which are pro-tumorigenic and promote tumor progression. In CRC, a microenvironment rich in TGF-β predominantly drives polarization toward the N2 phenotype.  

Pro-tumor neutrophils contribute to carcinogenesis through several mechanisms. They secrete proteases (such as elastase and MMP-9), facilitating tumor invasion and extracellular matrix degradation. They generate reactive oxygen species (ROS), leading to genetic damage, and promote angiogenesis through VEGF release.  

The formation of neutrophil extracellular traps (NETs) is another key mechanism. These extracellular DNA structures promote tumor cell adhesion, facilitate metastatic dissemination, and modulate the local immune response.  

Clinically, a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor prognosis in CRC, correlating with reduced overall and progression-free survival. Circulating neutrophils thus reflect systemic inflammation and tumor aggressiveness.

Interactions between neutrophils and tumor cells also contribute to therapeutic resistance, particularly by modulating responses to immune checkpoint inhibitors.  

Turning an inflammatory enemy into a therapeutic target  

Colorectal cancer is closely linked to chronic inflammatory processes. Neutrophils, once underestimated, now appear as central modulators of the tumor microenvironment, capable of influencing tumor growth, invasion, and metastatic spread.  

This review aimed to clarify their role in CRC progression and explore their translational potential. The data show that neutrophil infiltration and elevated NLR are robust prognostic markers, while the identified molecular mechanisms open new therapeutic avenues. Limitations include the heterogeneity of neutrophil phenotypes and the difficulty in distinguishing their protective versus deleterious roles depending on tumor context.  

Future perspectives include targeting the CXCR2 axis, inhibiting NET formation, or modulating N1/N2 polarization. Such strategies could integrate neutrophils into combination immunotherapy approaches, transforming an inflammatory player into a true therapeutic target.   

Read next: Colorectal cancer: detecting disease before the tumor appears?

About the author – Ana Espino
PhD in Immunology, specialized in Virology  
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.