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Tailoring Vascular-Immune Homeostasis via Manganese-DNA Complex-Armed Immunogenic Extracellular Vesicles for
Xue Jiang1,2, Lihuan Shang1,2, Xiaochun Chen1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Sun Yat-sen Memorial Hospital, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, 510120, China.
Abstract:
Harnessing the cGAS-STING DNA sensing pathway in dendritic cells (DCs) to enhance anti-tumor immunity in immunosuppressive pancreatic tumors remains a significant challenge. While manganese (Mn2+) enhances cGAS sensitivity to DNA, the precise mechanisms and potential of Mn-DNA complexes in this process are unclear. Here, this work introduces a strategy to encapsulate Mn-DNA complexes into DC-derived immunogenic extracellular vesicle (EVDC@Mn-DNA) to trigger robust anti-tumor immunity. This work shows that Mn2+ induces tumor cell-DNA transition to Z-DNA, strengthening cGAS binding and promoting its phase condensation for optimal activation in DCs. Using this newly developed Raft-Ultra method, this work engineers immunogenic EVs derived from tumor cell lysate-pulsed DCs, loaded with Mn-DNA complexes (EVDC@Mn-DNA). These EVs efficiently deliver Mn-DNA complexes to DCs, activating the cGAS-STING pathway both in vitro and in vivo. In animal models, EVDC@Mn-DNA administration enhances vascular function, as evidenced by increased blood flow and perfusion, improved anti-PD-L1 delivery, reduced hypoxia, and elevated endothelial cell-ICAM1 expression, which facilitates T cell adhesion. This approach expands the intratumoral population of activated DCs and T cells and promotes the formation of larger tertiary lymphoid structures, ultimately suppressing orthotopic pancreatic tumor growth. Overall, this EVDC@Mn-DNA strategy reprograms intratumoral DCs, restores vascular-immune homeostasis, and potentiates anti-tumor immunity in pancreatic cancer.
Insights
Engineered extracellular vesicles loaded with manganese-DNA complexes activate dendritic cells, enhancing anti-tumor immunity in pancreatic cancer models by reprogramming the tumor microenvironment.
Area of Science:
- Immunology
- Cancer Biology
- Nanotechnology
Background:
- Pancreatic tumors create an immunosuppressive environment, hindering anti-tumor immunity.
- The cGAS-STING DNA sensing pathway in dendritic cells (DCs) is crucial for immunity but challenging to activate in pancreatic cancer.
- Manganese (Mn2+) can enhance cGAS sensitivity, but its precise role with DNA complexes needs clarification.
Purpose of the Study:
- To develop a novel strategy using manganese-DNA complexes encapsulated in DC-derived extracellular vesicles (EVs) to activate the cGAS-STING pathway and enhance anti-tumor immunity.
- To investigate the mechanisms by which Mn2+ and DNA complexes activate cGAS in DCs.
- To evaluate the therapeutic potential of these engineered EVs (EVDC@Mn-DNA) in preclinical pancreatic cancer models.
Main Methods:
- Development of EVDC@Mn-DNA using the Raft-Ultra method, loading Mn-DNA complexes into EVs derived from tumor lysate-pulsed DCs.
- In vitro and in vivo assessment of cGAS-STING pathway activation in DCs upon EVDC@Mn-DNA treatment.
- Evaluation of tumor vascular function, immune cell infiltration, and tumor growth suppression in orthotopic pancreatic cancer models.
Main Results:
- Mn2+ induces Z-DNA formation, enhancing cGAS binding and activation.
- EVDC@Mn-DNA efficiently delivers Mn-DNA complexes to DCs, activating the cGAS-STING pathway.
- Treatment with EVDC@Mn-DNA improved vascular function (increased blood flow, perfusion; reduced hypoxia), enhanced anti-PD-L1 delivery, and promoted T cell adhesion.
- Increased intratumoral DCs and T cells, larger tertiary lymphoid structures, and suppressed tumor growth were observed.
Conclusions:
- EVDC@Mn-DNA is a promising strategy for reprogramming intratumoral DCs and restoring vascular-immune homeostasis.
- This approach potentiates anti-tumor immunity and suppresses pancreatic tumor growth.
- The findings highlight the therapeutic potential of engineered EVs for cancer immunotherapy.
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