Neutrophil extracellular traps in colorectal cancer: a paradoxical nexus of tumor defense and disease progression

Abstract

Neutrophil extracellular traps (NETs) are extracellular networks of decondensed chromatin and granular proteins generated by neutrophils in response to activating stimuli. Growing evidence indicates that NETs participate in colorectal cancer (CRC) development through their interactions with chronic inflammation, immune regulation, coagulation, and tumor progression. However, their biological effects vary across disease settings, and the regulatory mechanisms specific to CRC have not been fully clarified. This review examines the roles of NETs at different stages of CRC, including the transition from inflammation to cancer, primary tumor growth, metastatic spread, treatment resistance, and CRC-associated complications. We discuss CRC-related mechanisms of NET formation involving tumor-derived chemokines, stromal cells, microbial dysbiosis, oncogenic signals, and ROS-dependent pathways. Available evidence also suggests that NETs are not uniformly pro-tumorigenic. We therefore describe a “paradoxical nexus” in which their effects depend on tumor genotype, neutrophil phenotype, immune context, and the stimulus inducing NET formation. In addition, we review NET-related biomarkers, detection methods, and therapeutic approaches, while considering the evidence required for their clinical application and for context-specific treatment of CRC.