Cyborg and Bionic Systems | Nano-Immunotherapy Synergizes Ferroptosis and STING Activation for Metastatic Bladder Cancer

This study developed a pH/GSH dual-responsive nanodrug delivery system that significantly inhibits bladder and lung metastatic tumors by synergistically inducing ferroptosis and activating the STING pathway, while enhancing CD8+ T cell infiltration and long-term immune memory.

 

Literature Overview

This article, 'Nano-Immunotherapy Synergizing Ferroptosis and STING Activation in Metastatic Bladder Cancer', published in the journal Cyborg and Bionic Systems, reviews and summarizes a novel nano-immunotherapy strategy that enhances anti-tumor immune responses and suppresses metastatic bladder cancer progression through the synergistic induction of ferroptosis and activation of the STING pathway.

Background Knowledge

Bladder cancer is a common malignant tumor of the urinary system, with urothelial carcinoma (UC) accounting for over 90%. Based on tumor infiltration depth, it is classified into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). MIBC patients often require radical cystectomy or radiotherapy and chemotherapy, but approximately 50% eventually develop metastases, with a 5-year survival rate below 10%. Although immune checkpoint inhibitors (ICIs) have shown therapeutic benefits in some bladder cancer patients, the overall response rate remains at only 20%–30%, and reliable biomarkers to predict treatment outcomes are still lacking. Therefore, combination immunotherapy strategies have become a research hotspot. The STING pathway, a central component of innate immune activation, enhances dendritic cell (DC) activation and T cell responses through the release of damage-associated molecular patterns (DAMPs). In addition, lymph nodes serve as critical centers for immune responses, and their microenvironment significantly influences immunotherapeutic efficacy. This study presents a nanodelivery system based on Mannose-PEG-s-s-PCL and CDM-PEG-PCL that co-delivers the ferroptosis inducer IKE, the STING agonist diABZI, and the anti-PD-1 antibody. This system enables tumor microenvironment-responsive drug release and lymph node-targeted delivery, offering a novel synergistic strategy for bladder cancer immunotherapy.

 

 

Research Methods and Experiments

This study constructed a pH/GSH dual-responsive nanosystem, MPP@IKE-aPD-1/diABZI, which releases drugs under acidic or high-GSH conditions. The nanosystem was characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and flow cytometry. Drug release kinetics were evaluated by high-performance liquid chromatography (HPLC). Cellular uptake was analyzed by flow cytometry and confocal laser scanning microscopy (CLSM). Ferroptosis induction was assessed using C11-BODIPY, DCFH-DA staining, GSH detection, LDH release, and HMGB1 detection. Animal experiments included both orthotopic bladder cancer and lung metastasis models. Tumor targeting, anti-tumor efficacy, immune activation, and long-term immune memory were evaluated using in vivo imaging, tissue sectioning, immunohistochemistry, and flow cytometry.

Key Conclusions and Perspectives

• Under simulated tumor microenvironment conditions (pH 6.5 + 10 mM GSH), the nanosystem achieved cumulative release rates of 73.3% for diABZI and 83.4% for aPD-1, significantly higher than under physiological conditions (pH 7.4, <20%).
• The nanosystem substantially enhanced DC2.4 cell uptake efficiency (94.52%) under acidic/high-GSH conditions and promoted dendritic cell maturation, with CD80+CD86+ cell proportion increasing to 36.63%.
• In MB49 cells, MPP@IKE-aPD-1/diABZI effectively induced ferroptosis, demonstrated by significantly increased lipid peroxidation (P < 0.001), downregulated SLC7A11 expression, GSH depletion (85%), and elevated LDH release.
• In vivo experiments demonstrated that this nanosystem inhibited orthotopic bladder tumors by 94.5% and reduced lung metastatic nodules by 92%, extending the median mouse survival to 35 days.
• Mechanistic studies revealed that immunogenic cell death (ICD) induced by ferroptosis synergized with STING activation to enhance CD8+ T cell infiltration (156 cells/mm²) and Granzyme B expression, while blocking the PD-1/PD-L1 axis alleviated immunosuppression.
• This treatment regimen induced long-term immune memory, with central memory T cells (Tcm) and effector memory T cells (Tem) reaching 38.7% and 51.2%, respectively, effectively suppressing tumor recurrence in secondary tumor challenges.
• Activation of the cGAS-STING pathway via the nanosystem effectively induced type I interferon and proinflammatory cytokine release, remodeling the tumor immune microenvironment and enhancing anti-tumor immune responses.

Research Significance and Prospects

This study presents a synergistic, multi-mechanism nano-immunotherapy platform that offers a new strategy for improving the response rate of ICIs and overcoming immunotherapy resistance. Future research can focus on optimizing antibody conjugation efficiency, minimizing off-target distribution, and exploring the broad applicability of this system in other cancers. Additionally, this strategy holds promise for clinical translation, potentially offering personalized immunotherapy regimens for bladder cancer patients.

 

 

Conclusion

This study successfully developed a Mannose-modified, pH/GSH dual-responsive nanodelivery system that significantly enhances anti-tumor immune responses by synergistically inducing ferroptosis and activating the STING pathway. The system demonstrated excellent tumor- and lymph node-targeting capabilities in in vivo experiments, effectively suppressing primary and metastatic bladder tumor growth while inducing long-term immune memory. The mechanism involves the synergistic interaction between ferroptosis-induced immunogenic cell death and STING activation, offering new insights into overcoming resistance to immunotherapy. Future research will focus on the pharmacokinetics and safety profile of this system in humans, as well as its clinical translation potential, to provide improved combination immunotherapy strategies for bladder cancer patients.

 

Hang Huang, Fangdie Ye, Tianyue Liu, Qimeng Li, and Wei Chen. Nano-Immunotherapy Synergizing Ferroptosis and STING Activation in Metastatic Bladder Cancer. Cyborg and Bionic Systems.