Neutrophil extracellular traps in cancer: immune modulation, therapy resistance, and the dilemma of targeting

Abstract The release of extracellular DNA is a highly conserved mechanism across species. Extracellular traps released by neutrophils (NETs) represent a strategic defensive tool of the organism against pathogens, through their direct entrapment and killing, but also through the immunoadjuvant ability of their components. In this review, we discuss the involvement of NETs in cancer, from tumour initiation to recurrence, touching also on their role in cancer-associated comorbidities. We also discuss the emerging contribution of NETs in resistance to chemotherapy, radiotherapy and, particularly, immunotherapy, because of their suppression of cytotoxic immune responses and remodelling of the tumour microenvironment into an immune-tolerant niche. The therapeutic dilemma lies in whether targeting NETs to restore anti-tumour immunity may compromise the host’s defence against infections, an adverse effect that is far from negligible in patients who are often already immunocompromised. Furthermore, despite their widely recognized pro-tumoral functions, NETs have also been implicated in supporting anti-tumour immunity in specific contexts. The key challenge, therefore, lies in distinguishing between “bad” pro-tumoral NETs and “good” anti-microbial/anti-tumoral NETs, both for identifying reliable biomarkers and for developing more precise NET-based therapeutic targets.