Neutrophil extracellular traps in colorectal cancer: context-dependent roles from inflammatory carcinogenesis to liver metastasis and therapeutic targeting.

Colorectal cancer (CRC) develops and metastasizes within a microenvironment shaped by chronic inflammation, microbial exposure, stromal remodeling, and treatment pressure. Among the innate immune processes implicated in this setting, neutrophil extracellular traps (NETs) have attracted increasing attention. Initially described as antimicrobial structures, NETs have been implicated in several aspects of CRC biology, including inflammatory carcinogenesis, epithelial plasticity at the primary tumor site, gut-liver crosstalk, metastatic niche formation, and immune regulation. Experimental and translational studies suggest that they may influence tumor cell migration, extracellular matrix remodeling, hepatic colonization, and T-cell dysfunction, while also interacting with microbial and stromal signals in the liver. The available literature, however, does not support a uniformly deleterious role. Their biologic effect appears to vary with disease phase, anatomical site, neutrophil state, microbial context, and treatment exposure. In some settings, therapy-induced or early trap-associated responses may accompany tumor control rather than progression. In this review, we summarize current evidence on NETs in sporadic CRC, colitis-associated cancer (CAC), and colorectal cancer liver metastasis (CRLM), with particular attention to the gut-liver axis, immune microenvironment, biomarker development, and therapeutic intervention. We also discuss the major limitations of the field, including inconsistent detection strategies, overreliance on static or reductionist models, and limited spatially resolved human data. Overall, NETs may be better viewed as context-dependent effectors generated by distinct neutrophil states across different phases of disease.