Endoplasmic Reticulum Stress Nano-Orchestrators for Precisely Regulated Immunogenic Cell Death as Potent Cancer...

Area of Science:

• Biomedical Engineering
• Cancer Immunology
• Nanotechnology

Background:

• Immunogenic cell death (ICD) inducers are promising for cancer vaccines due to broad antigen presentation.
• Clinical translation is limited by low immunogenicity and potential tumorigenicity of ICD-induced tumor cells.

Purpose of the Study:

• To develop a nano-orchestrator targeting endoplasmic reticulum (ER) stress to optimize ICD for cancer vaccines.
• To precisely regulate the dose of ER stress for enhanced cancer vaccine efficacy.

Main Methods:

• Utilized an 808 nm laser with a clinical-range irradiation fluence (50–200 J cm⁻²) to trigger ER stress.
• Employed a nano-orchestrator to modulate ER stress and regulate the release of damage-associated molecular patterns (DAMPs) and antigens.
• Investigated the protein kinase R-like endoplasmic reticulum kinase (PERK)-C/EBP homologous protein (CHOP) pathway.

Main Results:

• A specific laser fluence (150 J cm⁻²) significantly increased dendritic cell maturation and antitumor T cell proliferation.
• The nano-orchestrator enhanced adjuvanticity and antigenicity by regulating ICD-induced DAMPs and promoting tumor cell apoptosis via the PERK-CHOP pathway.
• Optimized phototherapeutic dying tumor cells demonstrated a 100% success rate in prophylactic vaccination against tumor rechallenge in vivo.

Conclusions:

• Optimized ER stress via the nano-orchestrator effectively generates potent cancer vaccines from dying tumor cells.
• This strategy holds potential for developing in situ therapeutic tumor vaccines when combined with immune checkpoint inhibitors like anti-PD-L1.
• The findings offer insights into enhancing cancer immunotherapy by modulating endogenous immune responses.