癌症中的中性粒细胞胞外诱捕网：免疫调节、治疗抵抗与靶向策略的困境

癌症中的中性粒细胞胞外捕获网：免疫调节、治疗抵抗与靶向策略的困境

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

作者:Marta Brambilla, Anna Zanichelli, Valeria Cancila, Mario Paolo Colombo, Claudia Chiodoni, Sabina Sangaletti

期刊:Cell death & disease

摘要

细胞外DNA的释放是一种在不同物种中高度保守的机制。由中性粒细胞释放的细胞外陷阱（NETs）代表了机体对抗病原体的战略性防御工具，通过其直接捕获与杀灭作用，以及其组分具有的免疫佐剂能力。在本综述中，我们讨论了NETs在癌症中的作用，从肿瘤的发生到复发，并涉及其在癌症相关共病中的角色。此外，我们还探讨了NETs在化疗、放疗及尤其是免疫治疗中的新兴作用，原因在于它们对细胞毒性免疫反应的抑制以及肿瘤微环境的重塑，形成免疫耐受的微环境。治疗上的难题在于，靶向NETs以恢复抗肿瘤免疫是否可能削弱宿主对感染的防御，这在免疫功能已受损的患者中尤为重要，潜在的不良影响不可忽视。此外，尽管NETs的促肿瘤作用被广泛认可，但在某些特定情境下，NETs也被认为有助于支持抗肿瘤免疫。因此，关键的挑战在于区分“有害”的促肿瘤NETs与“有益”的抗微生物/抗肿瘤NETs，这对于开发可靠的生物标志物和更精确的NET靶向治疗策略具有重要意义。

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.

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