NETosis-PANoptosis Crosstalk in Colitis-Associated Colorectal Cancer: Mechanistic Links, Biomarkers, and Therapeutic Prospects

Colitis-associated colorectal cancer (CAC) is a serious long-term complication of inflammatory bowel disease (IBD) that develops through a chronic inflammation-dysplasia-carcinoma sequence. Persistent mucosal inflammation promotes epithelial barrier disruption, oxidative and genotoxic stress, dysregulated repair, and immune remodeling, thereby creating conditions that favor malignant transformation. Neutrophil extracellular trap (NET) formation and PANoptosis-an inflammatory programmed cell-death process integrating pyroptotic, apoptotic, and necroptotic machinery-represent two potentially interconnected components of this inflammatory environment. This narrative review examines the biological links between NETosis and PANoptosis in CAC, with emphasis on NET-derived nucleic acids, histones, myeloperoxidase, neutrophil elastase, reactive oxygen species, damage-associated molecular patterns, pattern-recognition receptor signaling, and cytokine networks. We further discuss microbiota-derived metabolites, candidate biomarkers, and therapeutic implications. Importantly, evidence is considered according to disease context: findings demonstrated in CAC are distinguished from mechanistic observations derived from IBD, sporadic colorectal cancer, and other inflammatory or tumor models, which are used to identify biologically plausible but not yet CAC-validated connections. Current data support bidirectional links between neutrophil activation and inflammatory epithelial cell death, but direct demonstration of a complete NETosis-PANoptosis feedback loop in human CAC remains limited. By bringing together these previously dispersed lines of evidence, this review clarifies where the NETosis-PANoptosis relationship is supported, where it remains inferential, and which molecular intersections may be most relevant for biomarker development and therapeutic investigation in CAC.