# Neutrophil Extracellular Traps in Exocrine Pancreatic Disease: A Comprehensive Review of Pathogenesis, Severity Stratification, and Therapeutic Targeting

## TL;DR

Neutrophil extracellular traps (NETs) are linked to both acute pancreatitis and pancreatic cancer, contributing to inflammation, blood clots, and tissue damage, and could be targeted for treatment.

## Contribution

This review identifies NETs as a unifying mechanism across exocrine pancreatic diseases and proposes therapeutic strategies to target them.

## Key findings

- NETs connect sterile inflammation with thromboinflammation and tissue remodeling in acute pancreatitis and pancreatic cancer.
- Early and excessive NET formation in acute pancreatitis correlates with severe clinical outcomes like microvascular thrombosis and organ dysfunction.
- Targeting NETs through DNase or upstream pathways may reduce thrombosis and tissue injury while rebalancing antitumor immunity in pancreatic cancer.

## Abstract

What are the main findings?
NETs act as a shared mechanistic thread across exocrine pancreatic diseases, linking sterile inflammation with thromboinflammation and tissue remodeling in both acute pancreatitis and pancreatic cancer.In acute pancreatitis, early and excessive NET formation aligns with more severe clinical trajectories and complications, including microvascular thrombosis, ductal obstruction, and systemic organ dysfunction.

NETs act as a shared mechanistic thread across exocrine pancreatic diseases, linking sterile inflammation with thromboinflammation and tissue remodeling in both acute pancreatitis and pancreatic cancer.

In acute pancreatitis, early and excessive NET formation aligns with more severe clinical trajectories and complications, including microvascular thrombosis, ductal obstruction, and systemic organ dysfunction.

What are the implications of the main findings?
NET-related circulating and tissue biomarkers (e.g., cfDNA-, MPO–DNA-, and CitH3-based readouts) may support earlier risk stratification and monitoring of therapeutic response in pancreatic disease.Therapeutically targeting NET biology (e.g., NET dismantling with DNase or upstream pathway inhibition such as PAD4/autophagy/redox signaling) is a rational strategy to reduce thrombosis and tissue injury and may help rebalance antitumor immunity in PDAC.

NET-related circulating and tissue biomarkers (e.g., cfDNA-, MPO–DNA-, and CitH3-based readouts) may support earlier risk stratification and monitoring of therapeutic response in pancreatic disease.

Therapeutically targeting NET biology (e.g., NET dismantling with DNase or upstream pathway inhibition such as PAD4/autophagy/redox signaling) is a rational strategy to reduce thrombosis and tissue injury and may help rebalance antitumor immunity in PDAC.

Neutrophil extracellular traps (NETs) are web-like DNA–protein structures released by activated neutrophils. Initially recognized for their antimicrobial roles, NETs are now known to drive sterile inflammation, thrombosis, and tissue remodeling. This review highlights their involvement in key pancreatic diseases, including acute pancreatitis (AP) and pancreatic ductal adenocarcinoma (PDAC). In AP, early NET formation correlates with disease severity and septic complications, contributing to acinar injury, microvascular thrombosis, ductal obstruction, and organ dysfunction. In PDAC, NETs shape a fibrotic and immune-resistant tumor microenvironment by promoting stromal activation, immune exclusion, metastasis, and hypercoagulability. Tumor- and stroma-derived signals sustain NET formation within this niche. We also discuss NET-related biomarkers for risk assessment and therapy monitoring, and explore therapeutic strategies that target NETs—ranging from their degradation with DNase to their inhibition of upstream pathways such as PAD4, autophagy, and oxidative signaling. Targeting NETs may also reduce their downstream effects on thrombosis and immune suppression. Overall, NETs emerge as critical drivers of pancreatic disease progression and represent promising therapeutic targets.