Innovative DCZCMC Platform: Dual Regulation of Cholesterol Dynamics and the cGAS/STING Pathway Activation to Combat
Jing Wang1,2, Xianchun Fu1,3, Han Zhang3
1Department of Urology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
Abstract:
Chemoresistance remains a daunting challenge in bladder cancer therapy, primarily driven by cholesterol-enriched rigid membranes that impede drug penetration and an immunosuppressive tumor microenvironment (TME) that evades immune surveillance. Herein, a biomimetic nanoplatform (DOX@COD-ZCM@CS, DCZCMC) is reported engineered to orchestrate metabolic-immunological crosstalk for synergistic reversal of chemoresistance. This integrated system comprises a Zn-Co metal-organic framework (Zn-Co-MOF, ZCM) core loaded with cholesterol oxidase (COD) and doxorubicin (DOX), surface-functionalized with chondroitin sulfate (CS) for tumor-specific targeting. Mechanistically, DCZCMC achieves three-tiered synergism: 1) COD-mediated cholesterol depletion (71.5% reduction, 111.2 vs 389.8 µm in the saline group) disrupts membrane rigidity, augmenting intratumoral drug retention to 87% (vs 39% with free DOX); 2) ZCM converts COD-generated H2O2 into cytotoxic hydroxyl radicals (·OH), realizing pathological cholesterol-to- reactive oxygen species (ROS) reprogramming for selective tumor oxidation; 3) Zn2+ release triggers mitochondrial DNA (mtDNA) leakage, activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to amplify interferon-β (IFN-β) and High Mobility Group Protein 1 (HMGB1) secretion, thereby driving dendritic cells (DCs) maturation and adaptive immune activation. In drug-resistant xenografts, DCZCMC exhibits exceptional antitumor efficacy (95.6% tumor suppression) without systemic toxicity. This self-amplifying "metabolic priming-immune activation" cascade represents a paradigm shift in overcoming chemoresistance, offering a transformative strategy for bladder cancer and other malignancies characterized by metabolic-immunological dysregulation.
Insights
This study introduces a novel nanoplatform to overcome chemoresistance in bladder cancer by depleting cholesterol and activating the immune system. The approach shows significant tumor suppression with no systemic toxicity.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Immunology
Background:
- Chemoresistance in bladder cancer is driven by cholesterol-rich membranes and an immunosuppressive tumor microenvironment (TME).
- Existing therapies struggle to penetrate rigid membranes and overcome immune evasion, limiting treatment efficacy.
Purpose of the Study:
- To develop a biomimetic nanoplatform (DOX@COD-ZCM@CS, DCZCMC) for synergistic reversal of chemoresistance in bladder cancer.
- To engineer a system that orchestrates metabolic-immunological crosstalk to enhance therapeutic outcomes.
Main Methods:
- A nanoplatform combining cholesterol oxidase (COD), doxorubicin (DOX), and a Zn-Co metal-organic framework (ZCM) was designed, with chondroitin sulfate (CS) for tumor targeting.
- The nanoplatform was evaluated for its ability to deplete cholesterol, generate reactive oxygen species (ROS), and activate the cGAS-STING immune pathway.
- Antitumor efficacy and systemic toxicity were assessed in drug-resistant xenograft models.
Main Results:
- DCZCMC effectively depleted tumor cholesterol by 71.5%, disrupting membrane rigidity and improving drug retention to 87%.
- The system reprogrammed cholesterol metabolism into ROS production and activated the cGAS-STING pathway via Zn2+ release, leading to immune cell activation.
- DCZCMC demonstrated 95.6% tumor suppression in vivo with no observed systemic toxicity.
Conclusions:
- The developed nanoplatform offers a novel strategy for overcoming chemoresistance by combining metabolic reprogramming with immune activation.
- This approach shows significant potential as a transformative therapy for bladder cancer and other metabolic-immuno dysregulated malignancies.
Related Concept Videos
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:15Drugs that Stabilize Microtubules
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...