# DNA delivered by lipid nanoparticles induces CD8+ T cell–dependent antitumor responses and enhances anti–PD-L1 therapy

## TL;DR

Injecting DNA in nanoparticles activates the immune system to fight tumors and improves cancer immunotherapy outcomes.

## Contribution

DNA encapsulated in lipid nanoparticles activates immune pathways and enhances anti–PD-L1 therapy in multiple cancer models.

## Key findings

- DNA-LNPs triggered strong cytokine production and CD8+ T cell recruitment in tumor models.
- DNA-LNPs prolonged survival in both ICI-responsive and ICI-resistant tumor models.
- DNA-LNPs synergized with anti–PD-L1 therapy to enhance antitumor effects.

## Abstract

Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of several cancer types. However, their effectiveness remains limited to a subset of patients, in part due to insufficient preexisting antitumor immunity. In this study, we hypothesized that intracellular delivery of noncoding dsDNA encapsulated in lipid nanoparticles (DNA-LNPs), which have recently been demonstrated to activate both STING and absent in melanoma 2 (AIM2) pathways, could enhance antitumor immune responses and potentiate ICI therapy. Using multiple animal models of cancer, including hepatocellular carcinoma, acute myeloid leukemia, melanoma, and melanoma lung metastasis, we show that DNA-LNP treatment triggered strong cytokine induction and robust CD8+ T cell recruitment to the tumor microenvironment. This immune activation mediated potent CD8+ T cell–dependent antitumor effects and prolonged animal survival across multiple models. Notably, empty LNPs did not elicit potent cytokine elevation or antitumor effects, suggesting that these responses are triggered by the activation of cytosolic DNA-sensing pathways. Moreover, DNA-LNPs synergized with anti–PD-L1, substantially extending animal survival in both ICI-responsive and ICI-resistant tumor models. These findings position DNA-LNPs as a promising immunotherapy strategy, either alone or in combination with ICI therapies, to enhance antitumor immunity across diverse cancer types.

We used various animal tumor models to demonstrate that delivery of DNA in nanoparticles boost the immune system’s attack on tumors and improves cancer immunotherapy effectiveness.