H₂S Self-Supplied Micelles Reverse Tumor-Immune Effector Cells Energy Metabolisms to Boost Breast Cancer...

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• Targeting tumor metabolism is a promising strategy for cancer immunotherapy.
• Current approaches face limitations due to compensatory energy pathways and poor drug delivery.

Purpose of the Study:

• To develop a hydrogen sulfide (H2S)-releasing nanoplatform for dual blockade of tumor cell metabolism.
• To enhance triple-negative breast cancer (TNBC) immunotherapy by normalizing the tumor microenvironment (TME).

Main Methods:

• A micellar nanoplatform (HA-ADT@W) was designed to deliver a glycolysis inhibitor (WZB117) and H2S.
• The system targets tumor cells overexpressing glutathione (GSH).
• Dual blockade of glycolysis and oxidative phosphorylation (OXPHOS) was achieved.

Main Results:

• The nanoplatform suppressed glucose uptake and reversed TME acidity.
• H2S inhibited compensatory OXPHOS by targeting cytochrome c oxidase.
• Metabolic rewiring induced immunogenic cell death and enhanced immune cell activity.

Conclusions:

• The H2S-self-supplying nanoplatform effectively enhances TNBC immunotherapy.
• This approach normalizes the TME and optimizes metabolic competition between tumor and immune cells.
• Smart nanomedicine offers a promising strategy for overcoming immunotherapy resistance.