Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma

Introduction: Immune checkpoint inhibitors (ICIs) have demonstrated promising therapeutic potential in head and neck squamous cell carcinoma (HNSCC). However, their clinical efficacy remains limited due to low response rates, largely attributed to the highly immunosuppressive tumor microenvironment (TME). Neutrophil extracellular traps (NETs) have recently been implicated in tumor progression and immune regulation. Therefore, this study aims to investigate the role of NETs in the TME and metastasis of HNSCC, and then to utilize cationic nanoparticles (cNP) to efficiently disrupt NETs in order to improve the immunosuppressive TME and inhibit metastasis, thereby suppressing the progression of HNSCC. Methods: (flow cytometry, immunofluorescence staining) experiments were conducted to investigate the effects of cationic nanoparticles (cNP) on NETs disruption, tumor cell migration, therapeutic efficacy and modulation of the TME. The underlying mechanism by which NET-DNA promotes HNSCC cell migration via CCDC25 was assessed using multiple approaches. Specifically, histological and immunohistochemical staining, western blotting, transfection, qRT-PCR, and transwell assays were performed. Results: B cells, while simultaneously inhibiting the infiltration levels of Treg cells and M-MDSCs, and promoting macrophage polarization from M2 to M1 types, significantly alleviating the immunosuppressive state of TME. Immunofluorescence staining further confirmed that cNP or cNP combined with anti-PD-1 therapy effectively reduced NET-DNA deposition in tumor tissue. Regarding migration mechanisms, NET-DNA can promote HNSCC cell migration through its receptor CCDC25. Discussion: This study reveals the key role of NETs in immune escape and metastasis of HNSCC and confirms that cNP disrupting NETs can synergistically enhance the efficacy of anti-PD-1 therapy, providing a new combination therapy strategy for HNSCC.