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 EspinoPhD 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.
