Near-Infrared-Triggered Photoresponsive Nanobombs Overcome Tumor Immunosuppression through Coordinated Pyroptosis...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Solid tumors create hypoxic and immunosuppressive environments, hindering conventional treatments.
• Reactive oxygen species (ROS)-induced pyroptosis shows potential for tumor microenvironment (TME) remodeling and boosting antitumor immunity.
• Mitochondrial autophagy repairs oxidative damage in cancer cells, reducing pyroptosis efficacy.

Purpose of the Study:

• To develop a near-infrared (NIR)-activated nanoplatform for targeted tumor eradication.
• To overcome limitations of current therapies by combining pyroptosis induction with mitochondrial autophagy inhibition.
• To investigate the synergistic effects of this dual-action strategy on the TME and antitumor immunity.

Main Methods:

• Engineered a "photocontrolled nanobomb" (PPLs) for NIR-activated ROS generation, pyroptosis induction, and autophagy blockade.
• Utilized lonidamine (LND) to inhibit HK2-driven mitochondrial autophagy.
• Assessed the reprogramming of the TME, including dendritic cell maturation and cytotoxic T lymphocyte infiltration.

Main Results:

• PPLs demonstrated NIR-activated ROS production, triggering Caspase-1-dependent pyroptosis and self-disintegration.
• Released LND effectively inhibited mitochondrial autophagy, amplifying oxidative damage and immunogenic cell death.
• The dual-action strategy successfully reprogrammed the immunosuppressive TME into a pro-inflammatory antitumor niche.

Conclusions:

• The NIR-responsive nanoplatform offers spatiotemporal tumor eradication.
• Deciphered the mechanistic synergy between pyroptosis and mitochondrial autophagy inhibition.
• Presents a promising strategy for combinatorial immunotherapy against solid tumors.