Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

Immunotherapy-based novel nanoparticles in the treatment of gastrointestinal cancer: Trends and challenges.

Gastrointestinal cancer (GIC) is the most common cancer with a poor prognosis. Currently, surgery is the main treatment for GIC. However, the high rate of postoperative recurrence leads to a low five-year survival rate. In recent years, immunotherapy has received much attention. As the only immunotherapy drugs approved by the Food and Drug Administration (FDA), immune checkpoint blockade (ICB) drugs have great potential in cancer therapy. Nevertheless, the efficacy of ICB treatment is greatly limited by the low immunogenicity and immunosuppressive microenvironment of GIC. Therefore, the targets of immunotherapy have expanded from ICB to increasing tumor immunogenicity, increasing the recruitment and maturation of immune cells and reducing the proportion of inhibitory immune cells, such as M2-like macrophages, regulatory T cells and myeloid-derived suppressor cells. Moreover, with the development of nanotechnology, a variety of nanoparticles have been approved by the FDA for clinical therapy, so novel nanodrug delivery systems have become a research focus for anticancer therapy. In this review, we summarize recent advances in the application of immunotherapy-based nanoparticles in GICs, such as gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic cancer, and described the existing challenges and future trends.

Safety and Efficacy of Wingspan Stenting for Severe Symptomatic Atherosclerotic Stenosis of the Middle Cerebral Artery: Analysis of 278 Continuous Cases.

OBJECTIVE: Our objective is to investigate the safety and long-term efficacy of the Wingspan stent (Boston Scientific, Natick, MA, USA) for treating severe atherosclerotic stenosis of the middle cerebral artery (MCA). METHODS: A total of 278 consecutive patients from our stroke database with clinical symptoms within the prior 90 days and intracranial atherosclerotic stenosis of 70% or above of the MCA were enrolled in this study between September 2012 and November 2014, and these patients were followed until the end of June 2015. The endpoint events included any stroke or death within 30 days after stenting and any subsequent ipsilateral ischemic stroke. RESULTS: Among the 278 enrolled patients, 277 patients (99.6%) successfully underwent stenting. The mean rate of stenosis decreased from 82.5 ± 7.9% to 9.0 ± 3.2% following treatment. Within 30 days after stenting, 12 patients (4.3%) experienced endpoint events, including 8 cases (2.9%) of hemorrhagic stroke and 4 cases (1.4%) of ischemic stroke; 2 perioperative deaths occurred. During 8-33 months of follow-up, 19 patients developed endpoint events. The 1- and 2-year endpoint event rates were 5.8% (95% confidence interval [CI], 5.0%-15.7%) and 7.2% (95% CI, 4.3%-10.1%), respectively. CONCLUSIONS: From this study, we can conclude that the treatment of severe symptomatic atherosclerotic stenosis of the MCA using the Wingspan stent was safe and effective and that the long-term stroke recurrence rate after stenting was low.