A Mitochondrion-Targeted NIR-II Modulator for Synergistic Ferroptosis-Immunotherapy.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Immunology

Background:

• Gastric cancer (GC) exhibits limited response to immune checkpoint inhibitors (ICIs) due to an immunosuppressive tumor microenvironment.
• Inducing immunogenic cell death (ICD) is crucial for overcoming this limitation and enhancing anti-tumor immunity.

Purpose of the Study:

• To develop novel nanoparticles for targeted therapy in gastric cancer.
• To investigate the potential of these nanoparticles in inducing immunogenic cell death and synergistic effects with ICIs.

Main Methods:

• Development of HD-FA nanoparticles encapsulating a novel mitochondrion-targeted NIR-II modulator (HD) within DSPE-PEG-FA.
• In vitro and in vivo evaluation of nanoparticle performance, including tumor accumulation, reactive oxygen species generation, and ferroptosis induction.
• Assessment of immune response modulation, including dendritic cell maturation, T-cell frequency, and myeloid-derived suppressor cell levels.

Main Results:

• HD-FA nanoparticles demonstrated superior spatiotemporal resolution, tumor accumulation, and minimal toxicity.
• Laser irradiation of HD-FA induced ferroptosis and oxidative stress in GC cells by inhibiting the SLC7A11/GSH/GPX4 axis, triggering ICD.
• HD-FA treatment led to significant antitumor activity in both primary and distant tumors, enhanced anti-tumor immunity, and improved immune cell profiles.

Conclusions:

• HD-FA nanoparticles represent a novel NIR-II modulator for gastric cancer immunogenic synergistic therapy.
• This approach holds significant potential for advancing the treatment of gastric cancer by overcoming ICI resistance.