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Updated: Jun 10, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Suppressing Pancreatic Cancer Survival and Immune Escape via Nanoparticle-Modulated STING/STAT3 Axis Regulation
Rui Li1, Renfa Liu1, Yunxue Xu1
1Department of Biomedical Engineering, College of Future Technology, National Biomedical Imaging Canter, Peking University, Beijing 100871, China.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8+ T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.
Insights
This study explores targeting the STING/STAT3 pathway in pancreatic cancer. Codelivery of STING agonists and STAT3 inhibitors via nanoparticles enhances anti-tumor immunity and improves outcomes for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Oncology
- Immunotherapy
- Nanomedicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is lethal and resistant to immunotherapy.
- The stimulator of interferon gene (STING) pathway offers immunotherapy potential, but PDAC cells show limited response.
- Signal transducer and activator of transcription 3 (STAT3) is overexpressed in PDAC, promoting tumor survival and immune evasion.
Purpose of the Study:
- To investigate the therapeutic potential of targeting the STING/STAT3 signaling axis in PDAC.
- To develop a novel nanomedicine approach for codelivering STING agonists and STAT3 inhibitors.
- To evaluate the efficacy of this approach in enhancing anti-tumor immunity and improving PDAC treatment outcomes.
Main Methods:
- Design of tumor-penetrating liposomes for codelivery of STING agonist and STAT3 inhibitor.
- In vitro and in vivo evaluation of the nanoparticles' effect on the STING/STAT3 signaling axis.
- Assessment of tumor growth inhibition, immune cell activation (NK cells, CD8+ T cells), and overall immune response.
Main Results:
- Codelivery nanoparticles effectively regulated the STING/STAT3 axis, inhibiting tumor proliferation and survival.
- Treatment led to significant activation of NK cells and CD8+ T cells, boosting innate and adaptive immunity.
- The approach demonstrated potential for overcoming immunotherapy resistance in PDAC.
Conclusions:
- Regulating the STING/STAT3 axis via codelivery nanoparticles is a promising strategy for PDAC treatment.
- This approach enhances anti-tumor immunity and may improve clinical outcomes for PDAC patients.
- Further research into STING/STAT3 targeted therapies could revolutionize pancreatic cancer treatment.
