ABSTRACT
AIMS: Checkpoint blockade immunotherapy is a promising therapeutic modality that has revolutionized cancer treatment; however, the therapy is only effective on a fraction of patients due to the tumor environment. In tumor immunotherapy, the cGAS-STING pathway is a crucial intracellular immune response pathway. Therefore, this study aimed to develop an immunotherapy strategy based on the cGAS-STING pathway. MATERIALS AND METHODS: The physicochemical properties of the nanoparticles EM@REV@DOX were characterized by TEM, DLS, and WB. Subcutaneous LLC xenograft tumors were used to determine the biodistribution, antitumor efficacy, and immune response. Blood samples and tissues of interest were harvested for hematological analysis and H&E staining. SIGNIFICANCE: Overall, our designed nanovesicles provide a new perspective on tumor immunotherapy by ICD and cGAS-STING pathway, promoting DCs maturation, macrophage polarization, and activating T cells, offering a meaningful strategy for accelerating the clinical development of immunotherapy. KEY FINDINGS: EM@REV@DOX accumulated in the tumor site through EPR and homing targeting effect to release REV and DOX, resulting in DNA damage and finally activating the cGAS-STING pathway, thereby promoting DCs maturation, macrophage polarization, and activating T cells. Additionally, EM@REV@DOX increased the production of pro-inflammatory cytokines (e.g., TNF-α and IFN-ß). As a result, EM@REV@DOX was effective in treating tumor-bearing mice and prolonged their lifespans. When combined with αPD-L1, EM@REV@DOX significantly inhibited distant tumor growth, extended the survival of mice, and prevented long-term postoperative tumor metastasis, exhibiting great potential in antitumor immunotherapy.
Subject(s)
Immunotherapy , Membrane Proteins , Nanoparticles , Nucleotidyltransferases , Animals , Nucleotidyltransferases/metabolism , Mice , Membrane Proteins/metabolism , Immunotherapy/methods , Nanoparticles/chemistry , Humans , Signal Transduction , Doxorubicin/pharmacology , Doxorubicin/administration & dosage , Cell Line, Tumor , Mice, Inbred C57BL , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/drug therapy , Neoplasms/pathology , Female , Xenograft Model Antitumor Assays , Immunogenic Cell Death/drug effectsABSTRACT
Prostate cancer (PC) is a malignancy with high morbidity and mortality. Bone metastasis is the main driver of short survival time and difficulties in the treatment and prevention of PC. The goal of this study was to explore the biological function of E3 ubiquitin ligase F-box only protein 22 (FBXO22) in PC metastasis and its specific regulation mechanism. According to transcriptome sequencing, FBXO22 was overexpressed in PC tissues (versus adjacent tissues) and bone tissues (versus biopsied bone tissues without bone metastases). Fbxo22 down-regulation reduced bone metastases and macrophage M2 polarization in mice. FBXO22 was down-regulated in macrophages, and polarization was observed by flow cytometry. Macrophages were co-cultured with PC cells and osteoblasts to assess PC cell and osteoblast activity. FBXO22 knockdown restored osteoblast capacity. FBXO22 ubiquitinated and degraded Krüppel-like factor 4 (KLF4), which regulated the nerve growth factor (NGF)/tropomyosin receptor kinase A pathway by repressing NGF transcription. Silencing of KLF4 mitigated the metastasis-suppressing properties of FBXO22 knockdown, whereas NGF reversed the metastasis-suppressing properties of KLF4 in vitro and in vivo. Cumulatively, these data indicate that FBXO22 promotes PC cell activity and osteogenic lesions by stimulating macrophage M2 polarization. It also degrades KLF4 in macrophages and promotes NGF transcription, thereby activating the NGF/tropomyosin receptor kinase A pathway.
Subject(s)
Bone Neoplasms , F-Box Proteins , Prostatic Neoplasms , Humans , Male , Mice , Animals , Nerve Growth Factor/metabolism , Tropomyosin/metabolism , F-Box Proteins/genetics , F-Box Proteins/metabolism , Prostatic Neoplasms/genetics , Signal Transduction , Receptors, Cytoplasmic and NuclearABSTRACT
Coking coals are the important raw materials for the iron and steel industries and play an important role on its sustainable development, especially on the stamp-charging coke making with the characteristics of increasing the bulk density. There is a significance on the reasonable usage of the coking coal resource with the reduced production cost, improved efficiency of the economy to develop the stamp-charging coke making technology. Important effects of the density of coking coal on the coking and caking properties were investigated. In the article, the maximum values of swelling pressure and variation of Laowan gas coal and Xinjian 1/3 coking coal, Longhu fat coal and Didao coking coal, which were mined at Shenyang and Qitaihe respectively, were investigated under different bulk densities during the coking. The results showed that when the values of density increased from 0.85 ton/m(3) to 1.05 ton/m(3), for the Laowan gas coal, swelling pressure variation and even the maximum value changed slightly. The swelling pressure was 3.63 KPa when the density was improved to 1.05 ton/m(3); for the Xinjian 1/3 coking coal, the values of swelling pressure changed significantly and the maximum values was 82.88 KPa with the density improved to 1.05 when the coal was heated to 600°C. The coke porosity, which was investigated by automatic microphotometer, decreased from 47.4% to 33.1% with the increasing of the density from 0.85 ton/m(3) to 1.05 ton/m(3), and the decreased value was 14.3%. Meanwhile, the pore structures of four cokes were characterized by an optical microscope.
