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

ABSTRACT Oral squamous cell carcinoma (OSCC) demonstrates limited response to immunotherapies due to immunosuppression and metastasis. This study presents an injectable pH/ROS‐dual‐responsive hydrogel co‐loaded with enoblituzumab (B7‐H3 blocker) and Cl‐amidine (NETs suppressor). The hydrogel, formed by boronic ester bonds and Schiff base linkages, ensures precise drug release within the acidic, high‐ROS tumor microenvironment (TME). Notably, its localized intratumoral delivery avoids intravenous administration's systemic toxicity and off‐target effects, enabling high intratumoral accumulation with minimal systemic exposure. In orthotopic and subcutaneous OSCC models, intratumoral administration significantly suppressed tumor growth compared to monotherapies or controls. This enhanced antitumor effect arises from synergistic TME reprogramming: Cl‐amidine inhibits NETs formation to reduce barriers and facilitate robust CD4 ⁺ /CD8 ⁺ T‐cell infiltration, while enoblituzumab, by targeting B7‐H3, restores cytotoxic T‐cell function and augments antibody‐dependent cellular cytotoxicity. Experimental evidence validates the suppression of OSCC invasion and metastasis through inhibition of B7‐H3 and NETs, which occurs by reversal of their induced epithelial‐mesenchymal transition (EMT). The hydrogel exhibits excellent biocompatibility without systemic toxicity. This TME‐responsive combination strategy offers a promising approach to enhance immunotherapy efficacy and overcome immune resistance in OSCC.