pH/ROS-Responsive Injectable Hydrogel Co-Loaded with B7-H3 Blocker and NETs Suppressor Boosts OSCC Synergistic...

Area of Science:

• Oncology
• Biomaterials Science
• Immunotherapy

Background:

• Oral squamous cell carcinoma (OSCC) exhibits poor response to immunotherapy due to tumor microenvironment (TME)-mediated immunosuppression and metastasis.
• Existing immunotherapies face challenges including systemic toxicity and limited efficacy in OSCC.
• Targeting immunosuppressive factors within the TME is crucial for enhancing antitumor responses.

Purpose of the Study:

• To develop an injectable, dual-responsive hydrogel for localized delivery of enoblituzumab (B7-H3 blocker) and Cl-amidine (NETs suppressor).
• To investigate the synergistic effects of this combination therapy in reprogramming the OSCC TME and overcoming immune resistance.
• To evaluate the efficacy of the hydrogel in suppressing OSCC growth, invasion, and metastasis.

Main Methods:

• Fabrication of a pH/ROS-dual-responsive hydrogel using boronic ester bonds and Schiff base linkages.
• Co-loading of enoblituzumab and Cl-amidine into the hydrogel for precise TME-triggered release.
• Intratumoral administration of the hydrogel in orthotopic and subcutaneous OSCC mouse models.
• Assessment of TME reprogramming, immune cell infiltration (CD4+/CD8+ T-cells), and tumor growth inhibition.
• Evaluation of metastasis suppression via inhibition of epithelial-mesenchymal transition (EMT).

Main Results:

• The hydrogel demonstrated precise drug release in the acidic, high-ROS TME, enabling high intratumoral accumulation with minimal systemic exposure.
• Intratumoral administration significantly suppressed OSCC tumor growth compared to monotherapies or controls.
• The combination therapy effectively inhibited neutrophil extracellular traps (NETs) formation and promoted CD4+/CD8+ T-cell infiltration.
• Enoblituzumab and Cl-amidine synergistically restored cytotoxic T-cell function and augmented antibody-dependent cellular cytotoxicity.
• The treatment suppressed OSCC invasion and metastasis by reversing EMT, with excellent biocompatibility and no observed systemic toxicity.

Conclusions:

• The pH/ROS-dual-responsive hydrogel co-delivering enoblituzumab and Cl-amidine is a promising strategy for OSCC treatment.
• This localized combination therapy effectively reprograms the immunosuppressive TME, enhancing immunotherapy efficacy.
• The approach overcomes immune resistance and suppresses OSCC progression, offering a potential clinical translation for refractory oral cancers.