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Tailoring vascular-immune homeostasis via magnesium-DNA complex-armed immunogenic vesicles for pancreatic cancer immunotherapy

ABSTRACT: Leveraging the cGAS-STING DNA sensing pathway in dendritic cells (DCs) for anti-pancreatic tumor immunity is challenging due to activation constraints, particularly in the context of pancreatic cancer's immunotherapeutic resistance. Recent research indicates that magnesium (Mn2+) enhances cGAS sensitivity to DNA, although the precise mechanism remains unclear. In this study, we demonstrate that the addition of Mn2+ increases the affinity of tumor cell-DNA binding to cGAS. Utilizing a Raft-Ultra method, we engineered immunogenic extracellular vesicles (EVs) derived from tumor cell lysate-pulsed DCs, loaded with Mn-DNA complexes (EVDC@Mn-DNA). These EVs efficiently deliver DNA to DCs, activating the cGAS-STING pathway both in vitro and in vivo. Animal experiments reveal that administering EVDC@Mn-DNA enhances vascular function, as evidenced by increased blood flow/perfusion, improved anti-PD-L1 delivery, reduced hypoxia, and elevated endothelial expression of the T cell adhesion molecule ICAM1. Furthermore, this treatment promotes the intratumor population of activated DCs and T cells and increases the sizes of tertiary lymphoid structures, thereby restraining orthotopic pancreatic tumor growth. Overall, our EVDC@Mn-DNA strategy activates intratumor DCs, restoring vascular-immune cell homeostasis and stimulating anti-tumor immunity in pancreatic cancer.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Pingpui Wong

PROVIDER: PXD051467 | iProX | Mon Apr 15 00:00:00 BST 2024

REPOSITORIES: iProX

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