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Updated: May 28, 2025
Intralymphatic Immunotherapy and Vaccination in Mice
Published on: February 2, 2014
Cascaded immunotherapy with implantable dual-drug depots sequentially releasing STING agonists and apoptosis inducers
Kai Li1, Xuan Yu1, Yanteng Xu2
1Laboratory of Biomaterials and Translational Medicine, Department of Ultrasound, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China.
Abstract:
Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for postsurgical adjuvant treatment of tumors. However, their limited effect duration hampers therapeutic effectiveness, necessitating prolonged administration of multiple doses that heightens infection risk and impacts patient compliance. Here, we develop an implantable dual-drug depot in a sandwich-like configuration, with a non-nucleotide STING agonist (MSA-2) in the outer layers of 3D-printed scaffolds and an immunogenic apoptosis inducer (doxorubicin, DOX) in the inner layer of electrospun fibers. We discover that MSA-2 can elicit endoplasmic reticulum stress-mediated and general immunogenic apoptosis of cancer cells. The stimulations with tumor-associated antigens and damage-associated molecular patterns from cancer cells, along with proinflammatory factors secreted by matured dendritic cells and M1-polarized macrophages, can depolymerize intracellular microtubules guiding activated STING trafficking towards lysosomes for degradation. Collectively, the dual-drug depots can initiate a long-lasting cascaded immunotherapy and chemotherapy, suppressing postsurgical tumor recurrence and metastasis.
Insights
This study introduces a dual-drug implant for sustained cancer immunotherapy. It combines a STING agonist and chemotherapy drug to effectively suppress postsurgical tumor recurrence and metastasis.
Area of Science:
- Oncology
- Immunotherapy
- Biomaterials
Background:
- Non-nucleotide stimulators of interferon gene (STING) agonists show potential for postsurgical tumor treatment.
- Limited duration of STING agonist action necessitates frequent dosing, increasing infection risk and reducing patient compliance.
Purpose of the Study:
- To develop an implantable dual-drug depot for sustained, combined immunotherapy and chemotherapy.
- To investigate the mechanism of action and therapeutic efficacy in suppressing postsurgical tumor recurrence and metastasis.
Main Methods:
- Fabrication of a sandwich-like dual-drug depot using 3D-printed scaffolds and electrospun fibers.
- Incorporation of a non-nucleotide STING agonist (MSA-2) and doxorubicin (DOX) into distinct layers.
- Evaluation of cancer cell apoptosis, immune cell activation, and tumor suppression in a postsurgical setting.
Main Results:
- MSA-2 induced endoplasmic reticulum stress and immunogenic cancer cell apoptosis.
- Tumor-associated antigens and damage-associated molecular patterns triggered STING degradation via microtubule depolymerization.
- The dual-drug depot demonstrated long-lasting cascaded immunotherapy and chemotherapy, significantly suppressing tumor recurrence and metastasis.
Conclusions:
- The developed dual-drug depot offers a promising strategy for effective postsurgical adjuvant cancer therapy.
- This approach overcomes the limitations of short-acting STING agonists, enhancing therapeutic outcomes and patient compliance.
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