Immunogenic Extracellular Vesicles Derived from Endoplasmic Reticulum-Stressed Tumor Cells: Implications as the Therapeutic Cancer Vaccine.

Tumor-derived extracellular vesicles (TDEs) have potential for therapeutic cancer vaccine applications since they innately possess tumor-associated antigens, mediate antigen presentation, and can incorporate immune adjuvants for enhanced vaccine efficacy. However, the original TDEs also contain immune-suppressive proteins. To address this, we proposed a simple yet powerful preconditioning method to improve the overall immunogenicity of the TDEs. This approach involved inducing endoplasmic reticulum (ER) stress on parental tumor cells via N-glycosylation inhibition with tunicamycin. The generated immunogenic TDEs (iTDEs) contained down-regulated immunosuppressive proteins and up-regulated immune adjuvants, effectively activating dendritic cells (DCs) in vitro. Furthermore, in vivo evidence from a tumor-bearing mouse model showed that iTDEs activated DCs, enabling cytotoxic T lymphocytes (CTLs) to target tumors, and eventually established a systemic antitumor immune response. Additionally, iTDEs significantly delayed tumor recurrence in a postsurgery model compared with control groups. These findings highlight the immense potential of our strategy for utilizing TDEs to develop effective cancer vaccines.

Self-immolative nanosensitizer for glutathione depletion- assisted sonodynamic therapy.

Background: Despite remarkable advances in sonodynamic therapy (SDT) of cancer, the low reactive oxygen species (ROS) quantum yield of the sonosensitizer remains a critical concern in glutathione (GSH)-overexpressing cancer cells. Methods: For enhanced SDT, we report hydrophilized self-immolative polymer (SIP)-decorated TiO2 nanoparticles (HSIPT-NPs) to achieve on-demand GSH depletion and ROS generation. Results: Upon intracellular delivery of HSIPT-NPs into hydrogen peroxide-rich cancer cells, SIP is degraded through electron transfer to produce GSH-depleting quinone methide, reprogramming GSH high cancer cells into GSH low phenotype. In the presence of ultrasound, compared to conventional TiO2 NPs, HSIPT-NPs induce significantly higher oxidative stress to cancer cells by incapacitating their antioxidant effects. SDT with HSIPT-NPs effectively inhibit tumor growth in mice via the synergistic effects of GSH depletion and ROS generation. Conclusion: On the basis of their ability to reprogram cancer cells, HSIPT-NPs offer considerable potential as a nanosensitizer for enhanced SDT.