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Life sciences · Journal article
Frontiers in Immunology · October 21, 2026
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Neutrophil extracellular traps (NETs), long recognized as effectors of innate host defense, are now firmly implicated in remodeling the tumor microenvironment and facilitating tumor progression. Tumor-associated NETs expose proteases, damage-associated molecular patterns, and self-DNA that activate protease-activated receptor 2 (PAR2) on tumor and stromal cells, engaging downstream cascades (Gαq/11-PLCβ-PKC-MEK-ERK, RhoA-ROCK, β-arrestin-biased signaling, and RTK transactivation), which jointly drive epithelial-mesenchymal transition, matrix degradation, and angiogenesis, ultimately favoring invasion and metastasis. Direct evidence that NET-derived proteases engage PAR2 on tumor or stromal cells rests, however, on a limited number of studies, and much of the literature concerns NETs or PAR2 individually rather than their coupling. We searched PubMed with structured queries combining “neutrophil extracellular traps”/”NETs”, “protease-activated receptor 2”/”PAR2”/”F2RL1”, and cancer-related descriptors, supplemented by citation tracing, with coverage through August 2026, and graded each mechanistic claim at claim level as strong, moderate, or emerging according to explicit criteria (see Literature search and evidence grading); findings supported for NETs or PAR2 alone are labeled as such throughout. The axis is documented most completely in breast, pancreatic, lung, and colorectal cancers, where tumor-type-specific drivers have been defined (dormant-cell reawakening in breast cancer, stromal reprogramming in pancreatic cancer, bypass of targeted therapy in lung cancer, and bidirectional signaling in colorectal cancer), whereas in biliary and cervical cancers only descriptive NET data are available; therapeutic strategies targeting the axis (PAD4 inhibitors, DNase I, PAR2 antagonists/antibodies, and combinations with immune checkpoint blockade) show preclinical promise. However, validated biomarkers of pathway activity and safety data for chronic PAR2 blockade are lacking. The NETs-PAR2 axis is an emerging targetable driver of tumor invasion, and biomarker-guided, tumor-type-aware clinical development is required to translate axis-directed therapy into the clinic.