Chimeric exosomes-derived immunomodulator restoring lymph nodes microenvironment for sensitizing TNBC immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunology

Background:

• Immunotherapy shows promise for triple-negative breast cancer (TNBC), but efficacy is limited in many patients.
• Dysfunctional dendritic cells (DCs) in the immunosuppressive lymph node (LN) microenvironment, linked to elevated reactive oxygen species (ROS) and lipid imbalance, hinder TNBC immunotherapy.
• Optimizing the LN microenvironment is crucial for enhancing immunotherapy response in TNBC.

Purpose of the Study:

• To develop a novel chimeric exosome-based immunomodulator to overcome immunotherapy resistance in TNBC.
• To restore DC function and improve the immunosuppressive LN microenvironment in TNBC.
• To enhance the efficacy of immunotherapy for TNBC by addressing ROS and lipid homeostasis.

Main Methods:

• Constructed a multifaceted immunomodulator using polysulfide bond-bridged mesoporous silica core, toyocamycin, and chimeric exosomes (DCs-derived exosomes and Salmonella outer membrane vesicles).
• Engineered the immunomodulator for enhanced LN homing via homologous targeting and chemokine guidance.
• Utilized ROS-responsive drug release to restore DC and LN immuno-microenvironment functions.

Main Results:

• The immunomodulator significantly improved TNBC responsiveness to immunotherapy.
• Potent inhibition of primary tumor growth and metastases was observed.
• A substantial increase in central memory T cells within LNs was achieved, promoting sustained antitumor immunity.

Conclusions:

• The developed immunomodulator effectively optimizes the LN microenvironment in TNBC.
• This strategy significantly enhances immunotherapy efficacy for TNBC by restoring DC function and immune memory.
• The study presents a promising approach for translational immunotherapy in TNBC treatment.