Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor...

Area of Science:

• Biomedical Engineering
• Cancer Immunology
• Nanotechnology

Background:

• Immunogenic cell death (ICD) is a promising cancer therapy, but its efficacy is often limited by adenosine (ADO) production, which suppresses the immune response and promotes tumor growth.
• Adenosine accumulation, a byproduct of ICD, creates an immunosuppressive tumor microenvironment, hindering therapeutic outcomes and facilitating metastasis.

Purpose of the Study:

• To develop an innovative strategy that activates ICD while simultaneously preventing the generation of immunosuppressive adenosine.
• To create a novel biohybrid system for targeted delivery and controlled release of an ICD inducer at tumor sites.
• To investigate the synergistic effects of the developed system combined with anti-PD-1 therapy for enhanced antitumor immunity and long-lasting memory.

Main Methods:

• Synthesis of ZIF-90 as an ATP-responsive core carrier encapsulating the CD73 inhibitor AB680.
• Coating the ZIF-90 core with an iron-polyphenol layer to form the ICD inducer (AZTF).
• Grafting AZTF onto prebiotic bacteria via esterification to create the engineered biohybrid (Bc@AZTF) for targeted tumor accumulation and acidic microenvironment-responsive release.
• Combination therapy of Bc@AZTF with anti-PD-1 (αPD-1) antibody.

Main Results:

• The engineered biohybrid Bc@AZTF effectively targets tumor sites and releases AZTF nanoparticles in response to the acidic tumor microenvironment.
• Bc@AZTF consumes intracellular ATP and inhibits the ATP-adenosine axis, significantly reducing adenosine accumulation and alleviating immunosuppression.
• The combination of Bc@AZTF and αPD-1 therapy demonstrated synergistic antitumor effects, enhancing tumoricidal immunity and establishing long-lasting immune memory.
• This approach effectively amplifies the ICD effect and overcomes adenosine-mediated immunosuppression.

Conclusions:

• The developed Bc@AZTF system represents a novel strategy for activating ICD while mitigating adenosine-induced immunosuppression.
• The synergistic combination of Bc@AZTF and anti-PD-1 therapy offers a potent approach for effective tumor eradication and management of tumor recurrence.
• This engineered biohybrid system presents a new paradigm for cancer immunotherapy by integrating ICD induction with adenosine metabolism modulation.