A tracheal stent integrating sustained release of paclitaxel/resiquimod and hyperthermia potentiates systemic antitumor immunity for enhanced malignant tracheal stenosis treatment.

Respiratory distress and tumor progression in malignant tracheal stenosis are both life-threatening. Anticancer drug-releasing tracheal stents achieve long-term localized chemotherapy to the tracheal tumor while dilating the airway; however, they cannot directly kill metastases. Furthermore, the anti-inflammatory stage during the chronic inflammatory response caused by stent placement reduces the effectiveness of stent-mediated chemotherapy. In this study, we propose a paclitaxel (PTX), resiquimod (R848) and Fe3O4 nanoparticles co-loaded tracheal stent (PTX/R848 stent), which exhibited self-expansion performance, magnetocaloric effect, and sustained co-release of PTX and R848, for local chemotherapy, magnetic hyperthermia (MH) and immunomodulation to enhance systemic immunity and antitumor effects synergistically. The PTX/R848 stent, in addition to relieving the stenosis, when combined with self-mediated MH, led to a decrease in HIF-1 levels and inflammatory responses, accompanied by increased macrophage infiltration in tumors. After 14 days of treatment, infiltrated macrophages were polarized from the anti-inflammatory M2 phenotype to the pro-inflammatory M1 phenotype, and the immune response to PTX- and MH-induced immunogenic cell death was promoted under the combined effects of released R848 and MH-mediated hypoxia alleviation. As a result, levels of effector T cells and pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) in both tumors and blood increased significantly, accompanied by promoted inhibition of both primary tumors and metastases, indicating the potentiation of systemic immunity and antitumor efficacy. Transcriptomic analysis also confirmed enrichment of immune-related pathways. In summary, the combined therapy mediated by the PTX/R848 stent achieves comprehensive and effective treatment of malignant tracheal stenosis and related metastases.