Metabolic-Immune Reprogramming via CuZnS@BSA Nanoregulators to Overcome Resistance in Triple-Negative Breast Cancer

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Triple-negative breast cancer (TNBC) exhibits therapeutic resistance due to high glutathione (GSH) levels and an immunosuppressive tumor microenvironment.
• Targeting GSH accumulation and enhancing anti-tumor immunity are crucial strategies for effective TNBC treatment.

Purpose of the Study:

• To design and evaluate biomimetic CuZnS@BSA nanoregulators for a pH-triggered therapeutic cascade against TNBC.
• To investigate the synergistic effects of GSH depletion, cuproptosis induction, and immune microenvironment remodeling in TNBC.

Main Methods:

• CuZnS@BSA nanoclusters were synthesized using self-assembly.
• In vitro studies assessed pH-responsive release, GSH depletion, ROS generation, and cuproptosis induction in 4T1 cells.
• In vivo studies evaluated anti-tumor efficacy, immune modulation, and anti-metastatic effects in TNBC mouse models, with and without PD-L1 blockade.

Main Results:

• The nanoregulator released H2S to deplete GSH, followed by Cu2+ release to induce cuproptosis, bypassing TNBC's apoptosis resistance.
• Released Zn2+ activated the cGAS-STING pathway, promoting CD8+ T cell infiltration and dendritic cell maturation, thereby remodeling the tumor microenvironment.
• Combination therapy with PD-L1 blockade significantly suppressed subcutaneous tumor growth and lung metastasis.

Conclusions:

• The developed nanoregulator effectively addresses TNBC resistance by combining metabolic reprogramming (GSH depletion) with immune activation.
• This approach establishes a link between metabolic reprogramming and systemic immune activation for enhanced TNBC therapy.
• Combination therapy shows potent anti-tumor and anti-metastatic effects, offering a promising strategy for TNBC treatment.