The Unseen Enemies: Harnessing the Role of Neutrophil Extracellular Traps in Breast Cancer Progression, Immune Evasion, and Treatment Resistance Publisher



Moradpanah S ; Forouzin S ; Samadi Nasab F ; Amirlatifi S ; Shirkosh P ; Marashi SM ; Khodakarim N
Source: Clinical Breast Cancer Published:2025

Abstract

Neutrophil extracellular traps (NETs) have emerged as central players in the tumor microenvironment, actively shaping breast cancer progression, immune evasion, and therapy resistance. Beyond their classical antimicrobial role, NETs serve as protumorigenic scaffolds that facilitate metastatic dissemination, promote a hypercoagulable state, and shield circulating tumor cells from immune surveillance. Critically, breast cancer therapies—including surgery, chemotherapy, and radiation—unintentionally exacerbate NET formation, amplifying systemic inflammation and fueling tumor recurrence. Surgical stress primes neutrophils for NETosis, creating an inflammatory milieu that disrupts wound healing and fosters metastatic seeding. Chemotherapeutic agents such as paclitaxel and doxorubicin trigger oxidative stress-driven NETosis, reinforcing tumor resilience and immune evasion. Similarly, radiation-induced DNA damage activates neutrophils, driving NET-mediated remodeling of the metastatic niche. Given the profound role of dysregulated NETosis in breast cancer pathogenesis, targeting NET formation represents a compelling therapeutic strategy. Emerging interventions—including peptidyl arginine deiminase 4 inhibitors, DNase therapy, and reactive oxygen species scavengers—offer promising avenues to disrupt NET-driven tumor progression, reduce post-treatment complications, and enhance therapeutic efficacy. This review provides a comprehensive analysis of the mechanistic crosstalk between NETosis and breast cancer therapy, highlighting its impact on disease trajectory and immune reprogramming. By delineating the intersection of NETs and oncologic treatments, we identify novel intervention strategies poised to improve clinical outcomes and long-term survival in breast cancer patients. © 2025 Elsevier B.V., All rights reserved.