Tumor-Associated Neutrophils and Their Impact on Colorectal Cancer

Role of Tumor-Associated Neutrophils in Colorectal Cancer

Tumor-associated neutrophils (TANs) are increasingly recognized as significant players in the tumor microenvironment (TME) of colorectal cancer. They can exhibit both pro-tumoral and anti-tumoral functions, depending on their polarization state. Studies have shown that TANs can facilitate tumor progression by promoting angiogenesis, immunosuppression, and metastasis through the secretion of various cytokines and growth factors (Mediators Inflamm, 2025). This duality reflects the complexity of the immune landscape in CRC, where the balance between inflammation and tumor promotion can dictate patient outcomes.

Research indicates that the presence of high levels of TANs is associated with poor prognosis in CRC patients. For instance, patients with elevated TAN infiltration levels often experience shorter overall survival rates (Mediators Inflamm, 2025). This suggests that TANs may serve as a potential biomarker for disease progression and response to therapy.

The infiltration of TANs into tumors is influenced by various factors, including tumor-derived signals and the immune landscape of the surrounding microenvironment. For example, TANs can be recruited to the tumor site through chemokines secreted by cancer cells, thereby exacerbating local inflammation and promoting tumor growth. Conversely, TANs can also exert anti-tumor effects by directly attacking cancer cells and enhancing adaptive immune responses (Tumour-Associated Neutrophils-Related Signatures Predict Prognosis and Indicate Immune Landscape in Colorectal Carcinoma, 2025).

Prognostic Significance of Neutrophil Infiltration Levels

The prognostic implications of TAN infiltration in CRC have been supported by various studies. For example, a recent study identified a prognostic model based on TAN-related genes, revealing that patients with elevated TAN levels had significantly worse survival outcomes compared to those with lower levels (Mediators Inflamm, 2025). This model was validated across multiple datasets, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases.

Furthermore, the prognostic value of TANs extends beyond survival rates. The analysis of immune cell infiltration using methods such as MCPcounter, xCell, and CIBERSORT has demonstrated that high levels of TANs are associated with increased tumor mutational burden (TMB) and microsatellite instability (MSI), both of which are critical indicators of response to immunotherapy (Mediators Inflamm, 2025). These findings underscore the potential of TANs not only as prognostic markers but also as predictors of treatment efficacy in CRC.

Identification of Key Genes Linked to Neutrophils in CRC

To further elucidate the role of TANs in CRC, researchers have focused on identifying specific genes associated with TAN infiltration. Using weighted gene co-expression network analysis (WGCNA), a set of genes correlated with neutrophil content has been determined (Mediators Inflamm, 2025). This analysis revealed a network of genes that not only contribute to the biology of TANs but also influence tumor behavior and patient outcomes.

The identified genes include those involved in immune responses, tumor progression, and inflammation. For instance, genes such as CXCL1 and MMP10 have been shown to correlate with increased TAN levels and poorer outcomes in CRC patients (Mediators Inflamm, 2025). The understanding of these genetic signatures allows for the development of targeted therapies aimed at modulating the activity of TANs within the TME.

Immune Landscape Alterations in CRC Patients with High TANs

The immune landscape in CRC is highly heterogeneous and is influenced by the presence of various immune cells, including TANs. In patients with high TAN infiltration, there is a notable alteration in the immune composition of the TME. This includes increased recruitment of immunosuppressive cells, such as regulatory T cells (Tregs), and a decrease in effector T cells, which are crucial for mounting an effective anti-tumor response (Mediators Inflamm, 2025).

Additionally, the presence of TANs is associated with increased expression of immune checkpoint molecules, such as PD-1 and CTLA-4, which can inhibit T cell activation and promote tumor immune evasion (Mediators Inflamm, 2025). This immune modulation highlights the complex interactions between TANs and other immune components in CRC, suggesting that therapeutic strategies targeting TANs may help to restore immune function and enhance the efficacy of existing treatments.

Therapeutic Implications of Targeting Neutrophils in Cancer Treatment

Given the dual roles of TANs in CRC, targeting these cells presents a promising therapeutic strategy. Current approaches to enhance anti-tumor immunity include the use of immune checkpoint inhibitors (ICIs) that block inhibitory pathways and promote T cell activation. However, the efficacy of these therapies can be hampered by the presence of TANs, which may promote tumor progression and immunosuppression (Mediators Inflamm, 2025).

Research indicates that modulating TAN behavior through specific interventions could enhance the efficacy of ICIs and other immunotherapies. For instance, agents that reprogram TANs from a pro-tumoral to an anti-tumoral phenotype may improve patient outcomes. Furthermore, combining TAN-targeting therapies with ICIs could provide a synergistic effect, leading to improved therapeutic responses in CRC patients (Mediators Inflamm, 2025).

Potential Strategies for Targeting TANs

1. Cytokine Modulation: Utilizing cytokines that promote TAN activation and enhance their cytotoxic functions.
2. Targeting Chemokine Receptors: Inhibiting the pathways that recruit TANs to tumors, thereby reducing their immunosuppressive effects.
3. Combination Therapies: Employing a dual approach that combines TAN modulation with existing immunotherapies.

FAQ

What are tumor-associated neutrophils (TANs)?
TANs are a type of immune cell found within the tumor microenvironment. They can have both pro-tumoral and anti-tumoral effects, depending on their state of activation and the surrounding signals.

How do TANs affect colorectal cancer prognosis?
Elevated levels of TANs in colorectal cancer are associated with poorer survival outcomes and can indicate a more aggressive tumor phenotype.

Can targeting TANs improve cancer treatment?
Yes, strategies to target or modulate TANs may enhance the effectiveness of immunotherapies and improve overall treatment responses in cancer patients.

What genes are associated with TANs in colorectal cancer?
Key genes linked to TANs include CXCL1 and MMP10, which are involved in inflammation and tumor progression.

What are the potential therapeutic strategies involving TANs?
Therapeutic strategies include cytokine modulation, targeting chemokine receptors, and combination therapies with immune checkpoint inhibitors.

References

1. Tumour-Associated Neutrophils-Related Signatures Predict Prognosis and Indicate Immune Landscape in Colorectal Carcinoma. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12162164/
2. Mediators of Inflammation. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12162164/
3. Uncovering Candidate Genes Associated with Cardiovascular Disease in Patients with Arteriovenous Fistula and End-Stage Renal Disease. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12162112/
4. Laparoscopic Surgery via an Inferior Pancreatic Border Approach for Median Arcuate Ligament Syndrome after Distal Gastrectomy: A Case Report. Retrieved from https://doi.org/10.70352/scrj.cr.25-0173
5. Integrin Alpha8 Beta1 (81): An In-Depth Review of an Overlooked RGD-Binding Receptor. Retrieved from https://doi.org/10.32604/biocell.2025.062325