Related Experiment Video
Updated: Jun 4, 2025
Intracranial Cannula Implantation for Serial Locoregional Chimeric Antigen Receptor CAR T Cell Infusions in Mice
Published on: February 24, 2023
Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung
Tianchuan Zhu1, Yuchen Xiao1, Zhenxing Chen1
1Center for Infection and Immunity, Guangdong Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, 519000, Guangdong, China.
Abstract:
Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors.
Insights
This study introduces anti-PD-L1 nanovesicles loaded with cGAMP to enhance chimeric antigen receptor-modified T (CAR-T) cell therapy. The nanovesicles target tumors, remodel the immunosuppressive microenvironment, and boost CAR-T cell efficacy against solid tumors.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Chimeric antigen receptor-modified T (CAR-T) cell therapy faces challenges from immunosuppressive tumor microenvironments in solid tumors.
- Existing therapies struggle with systemic inflammation and poor cellular uptake of therapeutic agents.
Purpose of the Study:
- To develop a novel nanovesicle system for targeted delivery of STING agonists to enhance CAR-T cell therapy.
- To investigate the efficacy of anti-PD-L1 nanovesicles loaded with cGAMP (aPD-L1 NVs@cGAMP) in remodeling the tumor microenvironment and improving CAR-T cell activity.
Main Methods:
- Pulmonary delivery of aPD-L1 NVs@cGAMP to target lung tumors.
- Utilizing the PD-1/PD-L1 interaction for selective delivery of STING agonists.
- Assessing the impact of STING signaling on immunosuppressive cells and CAR-T cell infiltration.
- Evaluating the role of the anti-PD-L1 fragment in preventing CAR-T cell exhaustion.
Main Results:
- Nanovesicles accumulated in the lung and delivered cGAMP to PD-L1-overexpressing cells, avoiding systemic inflammation.
- STING activation reduced immunosuppressive cells and promoted CAR-T cell infiltration.
- The anti-PD-L1 fragment prevented PD-L1 upregulation and CAR-T cell exhaustion.
- Combined therapy potently inhibited tumor growth and recurrence in lung cancer models.
Conclusions:
- aPD-L1 NVs@cGAMP effectively remodels the tumor microenvironment to enhance CAR-T cell therapy.
- This nanovesicle system shows promise as a CAR-T cell enhancer for solid tumors.
- Targeted delivery of STING agonists via nanovesicles offers a strategy to overcome CAR-T cell suppression.
