This study utilizes a pH/ROS-responsive hydrogel to enable synergistic targeting of B7-H3 and NETs, offering an innovative delivery strategy to overcome resistance to immune checkpoint inhibitors and impaired T-cell infiltration, which holds significant implications for the field of cancer immunotherapy.
Literature Overview
The article titled 'pH/ROS-Responsive Injectable Hydrogel Co-Loaded with B7-H3 Blocker and NETs Suppressor Boosts OSCC Synergistic Immunotherapy,' published in the journal Advanced Science, systematically investigates the mechanisms underlying the immunosuppressive microenvironment in oral squamous cell carcinoma (OSCC) and proposes a localized combinatorial immunotherapeutic strategy based on smart responsive hydrogels. The research team discovered that the combined overexpression of B7-H3 and accumulation of neutrophil extracellular traps (NETs) suppress T-cell infiltration and function. To address this, they developed an injectable hydrogel specifically responsive to the acidic and high reactive oxygen species (ROS) conditions of the tumor microenvironment (TME), enabling precise and controlled drug release. This platform not only significantly enhances antitumor efficacy but also reduces systemic toxicity, offering a novel approach to overcoming resistance in OSCC immunotherapy.Background Knowledge
1. OSCC is the most common malignant tumor in the head and neck region. Most patients are diagnosed at an advanced local stage. Despite standard treatments involving surgery combined with radiotherapy and chemotherapy, the 5-year survival rate remains only 50%–60%. Although PD-1/CTLA-4 inhibitors have shown efficacy in some patients in recent years, the overall response rate is less than 20%, often accompanied by severe immune-related adverse events (irAEs), highlighting the urgent need for more effective and safer immunotherapeutic strategies.
2. B7-H3, an emerging immune checkpoint molecule, is highly expressed in various solid tumors and closely associated with poor prognosis. In OSCC, it promotes immune escape by inhibiting CD8+ T-cell activity. Although the humanized antibody enoblituzumab shows potential in enhancing antibody-dependent cellular cytotoxicity (ADCC), its clinical application is limited by severe toxicities such as bleeding, indicating significant safety risks with systemic administration. Additionally, physical and immunological barriers in the tumor microenvironment, such as neutrophil extracellular traps (NETs), can physically block T-cell infiltration and suppress their function, leading to a 'cold tumor' phenotype that further diminishes immunotherapy responsiveness.
3. This study focuses on simultaneously targeting B7-H3-mediated T-cell functional suppression and NETs-mediated impairment of T-cell infiltration. By designing a pH/ROS dual-responsive hydrogel, the system enables specific drug release within the TME, avoiding systemic exposure. Furthermore, the localized delivery strategy is expected to reduce the toxicity associated with conventional intravenous administration, thereby improving the therapeutic index. This design elegantly integrates materials science with tumor immunology, offering a multidimensional solution to overcome immunotherapy resistance.
Research Methods and Experiments
The authors first confirmed through clinical sample analysis that B7-H3 is significantly overexpressed in OSCC tissues and positively correlated with neutrophil infiltration and NETs formation, while negatively correlated with CD8+ T-cell infiltration, revealing its dual role in immunosuppression. In vitro experiments further demonstrated that B7-H3 can directly promote NETs formation. Subsequently, a dual-responsive hydrogel was constructed based on oxidized dextran grafted with phenylboronic acid (POD) and dopamine-modified quaternized chitosan (CQCS). This system degrades rapidly under acidic and high ROS conditions via boronate ester and Schiff base linkages, enabling controlled drug release. In vitro release experiments showed significantly accelerated drug release under pH 5.0 + H₂O₂ conditions, while release was slow under physiological pH, confirming its TME-specific responsiveness.
In animal models, a humanized immune system mouse model (Hu-PBMC + NE) was employed, with CAL-27 cells injected sublingually to establish an orthotopic OSCC model, more accurately mimicking the human immune microenvironment. This model successfully reconstituted hCD3+ T cells and hCD66b+ neutrophils, providing a reliable platform for evaluating immunotherapeutic efficacy. A metastatic model was established via intravenous injection of tumor cells to assess treatment effects on metastasis. Multiple control groups were included—such as blank and monotherapy groups—ensuring experimental rigor.Key Conclusions and Perspectives
Research Significance and Prospects
This study presents a highly translatable local immunotherapeutic strategy for OSCC and other solid tumors with high B7-H3 expression. Traditional intravenous administration often causes systemic toxicity, whereas this localized delivery system enhances efficacy while significantly reducing side effects, aligning with the trend toward precision medicine. Future work could explore using this platform to deliver other immunomodulators or chemotherapeutic agents, extending its application to other 'cold tumor' types.
From a drug development perspective, this study underscores the critical role of delivery systems in improving the therapeutic index. Utilizing humanized mouse models for efficacy evaluation allows more accurate prediction of clinical responses, suggesting such models should be widely adopted in early-stage screening during new drug development.
Moreover, as an emerging immunosuppressive factor, NETs could serve as a potential biomarker for predicting immunotherapy response. Clinically, exploring the correlation between plasma levels of CitH3 or MPO-DNA complexes and treatment outcomes may aid in personalized therapy decisions.
Conclusion
This study integrates materials science and tumor immunology to develop an intelligent responsive hydrogel delivery system that enables synergistic targeting of B7-H3 and NETs, effectively overcoming two major barriers in OSCC immunotherapy—T-cell functional suppression and impaired infiltration. This strategy not only significantly enhances antitumor immune responses and suppresses primary and metastatic lesions but also demonstrates favorable safety, laying a solid foundation for clinical translation. From bench to bedside, this localized combinatorial treatment offers a new avenue for improving outcomes in OSCC patients, particularly those with locally advanced or recurrent disease. In the future, combining humanized animal models with advanced delivery technologies will accelerate the optimization of immunotherapeutic regimens, propelling precision cancer immunotherapy into a new era. This work also provides a valuable paradigm for modulating the immune microenvironment in other refractory solid tumors, offering broad scientific and clinical value.
