Tandem Chemoimmunotherapy by a Cascade-Responsive Molecular Prodrug

Area of Science:

• Oncology
• Immunotherapy
• Drug Delivery Systems
• Molecular Prodrugs

Background:

• Current immunotherapy response rates for many cancers remain limited, necessitating novel therapeutic strategies.
• The tumor microenvironment (TME) often exhibits immunosuppressive properties that hinder effective anti-cancer immune responses.
• Developing agents that can overcome TME-mediated immunosuppression is crucial for enhancing cancer treatment outcomes.

Purpose of the Study:

• To design and synthesize a novel cascade-responsive molecular prodrug for tandem chemoimmunotherapy.
• To investigate the prodrug's ability to induce immunogenic cell death (ICD) and modulate the TME.
• To evaluate the synergistic efficacy of this chemoimmunotherapy strategy against cancer in vitro and in vivo.

Main Methods:

• Synthesis of a molecular prodrug designed to release doxorubicin (DOX) and NLG919 sequentially.
• Assessment of DOX-induced immunogenic cell death (ICD) in tumor cells within a mildly acidic tumor microenvironment (TME).
• Evaluation of NLG919 release triggered by apoptosis-associated Caspase 3/7 activity to inhibit indoleamine 2,3-dioxygenase (IDO).
• In vitro and in vivo experiments to validate the prodrug's therapeutic efficacy and immune-activating properties.

Main Results:

• The molecular prodrug successfully released doxorubicin in the acidic TME, inducing ICD in tumor cells.
• Apoptosis-associated Caspase 3/7 activity led to the release of NLG919, effectively inhibiting IDO and reducing TME immunosuppression.
• The combination of ICD, antigen release, and immune activation resulted in a synergistic anti-tumor immune response.
• In vitro and in vivo studies confirmed the prodrug's significant efficacy in cancer treatment.

Conclusions:

• A novel cascade-responsive molecular prodrug enables effective tandem chemoimmunotherapy.
• This strategy leverages ICD and TME modulation to achieve synergistic anti-tumor effects.
• The developed prodrug shows promise as an efficient method to improve cancer treatment response rates.