LIFUS-driven engineered bacteria reprogram immunosuppressive niches via mechano-NOTCH signaling

Area of Science:

• Oncology
• Immunology
• Biotechnology
• Biomedical Engineering

Background:

• Solid tumors present significant stromal and immunological barriers, hindering T cell infiltration and anti-tumor activity.
• Current immunotherapies face challenges in overcoming the complex tumor microenvironment (TME).

Purpose of the Study:

• To engineer a novel Salmonella-based system for mechanical remodeling of the TME.
• To investigate the impact of LIFUS-activated GVs on T cell function and tumor control.
• To develop a mechano-priming strategy to enhance adoptive T cell therapies.

Main Methods:

• Engineered Salmonella VNP20009 to express gas vesicles (GVs).
• Utilized low-intensity focused ultrasound (LIFUS) to activate GVs, generating localized mechanical forces within tumors.
• Performed single-cell RNA sequencing to analyze T cell states and TME composition.
• Evaluated the efficacy of the mechano-priming approach in preclinical tumor models.

Main Results:

• LIFUS-activated GVs remodeled the TME by reducing cancer-associated fibroblasts (CAFs) and matrix density.
• Disruption of CAF-CD8+ T cell communication via the Notch1-Jagged1 axis was observed.
• Enhanced intratumoral CD8+ T cell infiltration, cytotoxic effector function, and cytokine production.
• Mechano-priming improved CD8+ T cell cytotoxicity, reduced exhaustion, and led to durable tumor control and extended survival.

Conclusions:

• LIFUS-activated GVs offer a novel strategy for biomechanical remodeling of the TME.
• This approach enhances T cell infiltration and effector function, overcoming tumor-induced immunosuppression.
• Mechano-priming with LIFUS-driven GVs represents a promising enhancement for adoptive T cell therapies.