Exosome transportation-mediated immunosuppression relief through cascade amplification for enhanced apoptotic body vaccination.

Cancer vaccines represent the most promising strategies in the battle against cancers. Eliciting a robust therapeutic effect with vaccines, however, remains a challenge owing to the weak immunogenicity of autologous tumor antigens and highly immunosuppressive microenvironment. In the present study, we constructed CpG oligodeoxyribonucleotide (CpG ODN)-loaded cancer cell apoptotic bodies (Abs) as cancer vaccines for enhanced immunotherapy through cascade amplification-mediated immunosuppression relief. Abs that contain an abundant source of tumor-specific neoantigens and other tumor-associated antigens (TAAs) can be regarded as vaccines with higher immunogenicity. The de novo synthesized Abs-CpG could target and polarize macrophages to improve the immunosuppressive microenvironment. More importantly, we found that the effect of immunosuppression relief was cascade amplified, which was mediated by M1 macrophage-derived exosome transportation. Our results showed that CpG ODN polarized macrophages to M1 type and produced a large amount of TNF-α, which then activated cell division control protein 42 (Cdc42). Interestingly, we found that exosomes from M1 macrophages delivered Cdc42 and CpG to adjacent macrophages and further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by Abs-CpG with macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved, which then enhanced the performance of cancer vaccine therapy. Thus, we propose that a strategy of combining the Abs-based vaccine platform with the immunomodulatory approach represents the next generation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: 1. We discovered a relieving strategy for tumor immunosuppressive microenvironment: Abs-CpG polarized macrophages to M1 type, and M1 macrophage-derived exosomes delivered Cdc42 and CpG to adjacent macrophages, which then further enhanced the phagocytosis of adjacent macrophages by positive feedback. Through cascade amplification induced by the transfer of macrophage exosomes, the immunogenicity and immunosuppressive microenvironment were greatly improved. 2. As a vaccine, Abs contained both tumor-specific neoantigens and other tumor-associated antigens with higher immunogenicity and high clinical transformability.

Improving the Therapeutic Efficiency of Hypoxic-Activated Prodrugs by Enhancing Hypoxia in Solid Tumors.

The low sensitivity of hypoxic regions in solid tumors to radiotherapy and chemotherapy remains a major obstacle to cancer treatment. By taking advantage of hypoxic-activated prodrugs, tirapazamine (TPZ), generating cytotoxic reductive products and the glucose oxidase (GOx)-based glucose oxidation reaction, we designed a nanodrug-loading system that combined TPZ-induced chemotherapy with GOx-mediated cancer-orchestrated starvation therapy and cancer oxidation therapy. In this work, we first prepared mesoporous silica (MSN) loaded with TPZ. Then, in order to prevent the leakage of TPZ in advance, the surface was coated with a layer of carMOF formed by Fe3+ and carbenicillin (car), and GOx was adsorbed on the outermost layer to form the final nanosystem MSN-TPZ@carMOF-GOx (MT@c-G). GOx could effectively consume oxygen and catalyzed glucose into gluconic acid and hydrogen peroxide. First, the generated gluconic acid lowered the pH of tumor tissues, promoted the decomposition of carMOF, and released TPZ. Second, oxygen consumption could improve the degree of hypoxia in tumor tissues, so that enhanced the activity of TPZ. Furthermore, GOx could generate cancer-orchestrated starvation/oxidation therapy. Therefore, our study provided a new strategy that TPZ combined with GOx achieved starvation/oxidation/chemotherapy for enhancing anticancer effects in hypoxic regions.

Therapeutic exosomal vaccine for enhanced cancer immunotherapy by mediating tumor microenvironment.

Tumor immunotherapy has been convincingly demonstrated as a feasible approach for treating cancers. Although promising, the immunosuppressive tumor microenvironment (TME) has been recognized as a major obstacle in tumor immunotherapy. It is highly desirable to release an immunosuppressive "brake" for improving cancer immunotherapy. Among tumor-infiltrated immune cells, tumor-associated macrophages (TAMs) play an important role in the growth, invasion, and metastasis of tumors. The polarization of TAMs (M2) into the M1 type can alleviate the immunosuppression of the TME and enhance the effect of immunotherapy. Inspired by this, we constructed a therapeutic exosomal vaccine from antigen-stimulated M1-type macrophages (M1OVA-Exos). M1OVA-Exos are capable of polarizing TAMs into M1 type through downregulation of the Wnt signaling pathway. Mediating the TME further activates the immune response and inhibits tumor growth and metastasis via the exosomal vaccine. Our study provides a new strategy for the polarization of TAMs, which augments cancer vaccine therapy efficacy.

Biomimetic Platform Based on Mesoporous Platinum for Multisynergistic Cancer Therapy.

Photothermal therapy (PTT) using nanoparticles is one of the research hotspots in the field of cancer therapy. However, the thermal resistance of tumor cells and the elimination of nanoparticles by the body's immune system reduce their therapeutic effect. Therefore, it is essential to reduce heat resistance, improve their biocompatibility, and reduce the clearance of the immune system. In this work, we constructed a biomimetic platform for cancer therapy based on heat shock protein (HSP) inhibitors, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG))-loaded and platelet membrane (PM)-coated mesoporous platinum nanoparticles (MPNPs). First, MPNPs with the properties of chemotherapy and PTT were synthesized to load 17-DMAG (17-DMAG/MPNPs). Then, they were coated with PM for tumor targeting and improved biocompatibility to obtain the final bionic nanotherapy platform 17-DMAG/MPNPs@PM. The results in vivo and in vitro showed that 17-DMAG/MPNPs@PM could accumulate in the tumor and effectively inhibit the growth of tumor cells. Therefore, the biomimetic nanotherapy system is expected to provide new ideas for cancer treatment.