Nano-bionic bacteria armed adoptive macrophage therapy against bladder cancer

Area of Science:

• Oncology
• Immunotherapy
• Nanomedicine

Background:

• Bladder cancer presents limited treatment options, often hindered by poor immune cell activity and a suppressive tumor microenvironment.
• Adoptive cell therapy shows promise but faces challenges in efficacy due to intrinsic antitumor limitations and immunosuppression.

Purpose of the Study:

• To develop a novel living adoptive macrophage therapy for bladder cancer using nano-bionic bacteria.
• To engineer macrophages to overcome tumor immunosuppression and enhance antitumor immunity.

Main Methods:

• Synthesized hollow manganese dioxide (MnO2) nanoparticles loaded with an adenosine inhibitor and coated with E. coli membranes.
• Engineered macrophages (Mac@ABMn) were activated via the STING pathway using LPS and Mn2+ ions.
• Evaluated the therapy's efficacy in a subcutaneous bladder cancer model and in combination with BCG or anti-PD-L1 therapy.

Main Results:

• Engineered macrophages infiltrated tumors, activated the STING pathway, and promoted an M1-like antitumor phenotype.
• The therapy counteracted immunosuppression by releasing adenosine inhibitors and generating oxygen, while also stimulating immune cells.
• Mac@ABMn therapy significantly enhanced antitumor immunity, increased CD4+ and CD8+ T cell infiltration, and showed synergistic effects with existing immunotherapies, leading to superior tumor control.

Conclusions:

• Developed a novel macrophage-based therapy (Mac@ABMn) for bladder cancer by engineering macrophages with nano-bionic bacteria.
• This therapy sustains an anti-tumor M1 phenotype, alleviates tumor hypoxia, and scavenges immunosuppressive adenosine.
• The engineered macrophages reprogram the tumor microenvironment, enhancing anti-tumor immunity and demonstrating significant synergistic efficacy with standard immunotherapies.