At the AACR 2026, new data challenged the traditional view of tumor necrosis as a passive process, demonstrating that neutrophil extracellular traps (NETs) actively drive necrosis and metastatic progression in colorectal cancer. The study provides both clinical and preclinical evidence that targeting NET formation may represent a novel strategy to limit tumor spread.
Background
Tumor necrosis is widely recognized as a marker of aggressive disease and poor prognosis across multiple cancer types, including colorectal cancer. However, necrosis has generally been considered a passive consequence of rapid tumor growth, hypoxia, and insufficient blood supply, rather than an active, targetable biological process.
Recent evidence has suggested that neutrophils, particularly through the formation of neutrophil extracellular traps, may play a more direct role in tumor biology. NETs are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils. While originally described as part of the innate immune response to infection, NETs have increasingly been implicated in cancer progression, including tumor growth, immune evasion, and metastasis.In this study, investigators sought to determine whether NETs actively contribute to tumor necrosis and metastatic behavior in colorectal cancer, using both human specimens and mechanistic preclinical models.
Methods
The study combined analyses of human samples with experimental modeling to evaluate the role of NETs in colorectal cancer progression. Blood samples from patients with colorectal cancer were analyzed to characterize neutrophil populations and their capacity for NET formation. Tumor specimens from primary colorectal cancer and colorectal liver metastases underwent histologic and immunofluorescent analysis to assess NET accumulation and spatial relationship with necrotic regions.
Advanced molecular profiling techniques, including single-cell RNA sequencing and spatial transcriptomics, were used to examine transcriptional programs associated with NET-rich tumor environments.
In parallel, a mismatch-repair-proficient orthotopic colorectal cancer model was developed using AKPS organoids, incorporating key oncogenic alterations including APC loss, KRAS G12D mutation, TP53 loss, and SMAD4 loss. These organoids were implanted via colonoscopic injection to mimic disease progression in vivo.
Genetic and pharmacologic approaches were then applied to inhibit NET formation and evaluate the impact on tumor necrosis and metastatic burden.
Study Design
This study integrated clinical observations with mechanistic validation in preclinical systems. In human samples, the investigators examined circulating neutrophil populations and tumor tissue architecture to identify patterns associated with NET formation and necrosis.A key feature of the design was the focus on both primary tumors and metastatic lesions, particularly colorectal liver metastases, allowing assessment of how NET-associated processes evolve during disease progression. The orthotopic mouse model provided a controlled system to study dynamic changes in neutrophil behavior, bone marrow activity, and tumor microenvironment over time. By combining genetic and pharmacologic inhibition strategies, the investigators were able to directly test whether NET formation is causally linked to necrosis and metastasis.
Results
In patients with colorectal cancer, circulating neutrophils showed an increased tendency toward NET formation. Notably, an expanded CD177-low neutrophil subset was identified, which retained strong NET-forming capacity but exhibited reduced ability to extravasate into tissues.Histologic and immunofluorescent analyses revealed abundant NET accumulation within necrotic regions of tumors. These NETs were frequently observed as intravascular deposits, suggesting a direct interaction with tumor vasculature and microenvironment. Importantly, the extent of tumor necrosis correlated with metastatic disease, independent of tumor size, reinforcing the clinical relevance of necrosis as more than a simple byproduct of tumor growth.
At the molecular level, NET-rich necrotic tumors exhibited activation of transcriptional programs associated with aggressive disease behavior. These included pathways related to myelopoiesis, driven by factors such as CSF1, CXCL2, and CXCL12, as well as hypoxia signaling, cellular migration, and epithelial-to-mesenchymal transition. Together, these features are strongly linked to increased metastatic potential.
In the orthotopic AKPS colorectal cancer model, tumor progression was accompanied by rising circulating neutrophil levels, skewing of bone marrow activity toward myelopoiesis, and increasing NET deposition within necrotic tumor regions. This temporal relationship supported a dynamic role for neutrophils and NETs in shaping tumor biology over time.
Critically, when NET formation was inhibited through genetic or pharmacologic approaches, there was a marked reduction in intratumoral necrosis. This was accompanied by a significant decrease in metastatic burden, providing direct evidence that NETs are not merely associated with necrosis, but actively drive both necrosis and metastatic progression.
Key Findings
This study demonstrates that neutrophil extracellular traps are active mediators of tumor necrosis in colorectal cancer, rather than passive byproducts of tumor growth. The presence of NETs within necrotic regions suggests a direct mechanistic link between innate immune activity and tumor tissue destruction.
Importantly, NET-rich tumor environments are associated with transcriptional programs that promote metastasis, including hypoxia signaling, epithelial-to-mesenchymal transition, and enhanced cellular migration. This positions NETs as key contributors to metastatic evolution.
The identification of a specific neutrophil subset with strong NET-forming capacity highlights the complexity of the immune landscape in colorectal cancer and suggests potential biomarkers for disease progression.Perhaps most significantly, inhibition of NET formation reduced both tumor necrosis and metastatic spread in preclinical models, providing proof-of-concept for a therapeutic strategy targeting this pathway.
Conclusion
Presented at the AACR 2026, this study reframes tumor necrosis as an active immunopathologic process driven by neutrophil extracellular traps in colorectal cancer. Rather than being an unavoidable consequence of tumor growth, necrosis appears to play a functional role in promoting metastasis.By demonstrating that NET inhibition can reduce both necrosis and metastatic spread, the findings open a new therapeutic avenue focused on modulating innate immune processes within the tumor microenvironment. As research continues to explore the role of neutrophils in cancer biology, targeting NET formation may emerge as a novel strategy to limit disease progression and improve outcomes for patients with colorectal cancer.