Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment.

Area of Science:

• Biomaterials Science
• Cancer Therapeutics
• Immunology

Background:

• Combination chemoimmunotherapy shows promise but is limited by side effects and variable response rates.
• Developing localized drug delivery systems can improve cancer treatment efficacy and safety.
• Targeting tumor microenvironment and immune checkpoints is crucial for effective cancer therapy.

Purpose of the Study:

• To fabricate an in situ-formed therapeutic silk-chitosan composite scaffold for controlled local release of doxorubicin (DOX) and JQ1.
• To investigate the synergistic anticancer effects and immune-triggering mechanisms of the DOX-JQ1@Gel.
• To evaluate the potential of this localized approach to improve objective response rates and minimize systemic toxicity.

Main Methods:

• Fabrication of a pH-degradable silk-chitosan composite scaffold (DOX-JQ1@Gel).
• In situ formation and characterization of the therapeutic scaffold.
• Evaluation of drug release kinetics in a tumor microenvironment.
• Assessment of immunogenic cell death, antigen release, and PD-L1 blockade.
• In vivo local injection and efficacy studies for synergistic cancer therapy.

Main Results:

• The DOX-JQ1@Gel scaffold demonstrated controlled release of doxorubicin and JQ1 in a weak acidic tumor microenvironment.
• Released doxorubicin induced direct tumor cell killing and immunogenic cell death, activating antitumor immunity.
• JQ1 enhanced antitumor immunity through PD-L1 checkpoint blockade, complementing chemotherapy-induced immune responses.
• Local injection of DOX-JQ1@Gel showed synergistic therapeutic effects against cancer.

Conclusions:

• The developed silk-chitosan scaffold enables localized co-delivery of chemotherapy and immunotherapy agents.
• This approach effectively triggers antitumor immunity and enhances treatment efficacy.
• The localized delivery system holds potential for improving cancer treatment outcomes with reduced systemic side effects.