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ACS Nano Qiu Wenxiu/Zhou Ying of Wuhan University of Science and Technology et al. activated innate immunity for local and systemic immunotherapy through STING signal amplifiers

 Last Update: 2022-10-20
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iNature

A limited
number of patients benefit from acquired immunotherapy.
Interferon gene-stimulating factor (STING) signaling activation is an important component of enhancing innate immunity and has been used to enable broad-spectrum immunotherapy
.

On October 3, 2022, Qiu Wenxiu and Zhou Ying of Wuhan University of Science and Technology and Xiong Yuan of Huazhong University of Science and Technology jointly published a paper entitled "Activating Innate Immunity by a STING Signal Amplifier for Local and Systematic" online at ACS Nano (IF=18).
Immunotherapy", which shows that innate immunity is activated by STING signal amplifiers for local and systemic immunotherapy
.
M@P@ HA nanoparticles, which act as STING signal amplifiers, are constructed to enhance innate immunotherapy
.
Simply put, when M@P@HA target tumor cells, the nanoparticles break down along with Mn2⁺ and activate the release
of protoporphyrin (PpIX).
Under light irradiation, the reactive oxygen species produced disrupt cellular redox homeostasis, causing cytoplasmic leakage of damaged mitochondrial double-stranded (ds) DNA, which is the initiator of STING signaling
.

At the same time, Mn2⁺ as an immunomodulator can significantly increase the activity of STING signal-related proteins, such as cyclic GMP-AMP synthase (cGAS) and STING, and further amplify the STING signal
of tumor cells.
Subsequently, STING signals from tumor-associated macrophages (TAMs) are also activated by capturing dsDNA and Mn2+ that escape from tumor cells, thereby enhancing innate immunity
.
In conclusion, the study found that in tumors with low immunogenicity, M@P@HA by amplifying the STING signal of tumor tissue, not only can it activate innate immunity, but also activate CD8⁺T cell infiltration in cascade
.

Immunotherapy is the dawn of patients with unresectable tumors
.
At present, clinical immunotherapy mainly relies on acquired immunity, such as anti-tumor T cell therapy and immune checkpoint blockade (ICB) immunotherapy
.
However, due to tumor heterogeneity, individual variability, and low immunogenicity of tumors, the number of patients benefiting from acquired immunotherapy is very limited
.
Organisms are born with strong innate immunity that can be used to achieve broad-spectrum immunotherapy
.
At the same time, by activating innate immunity, immunosuppressed "cold tumors" are transformed into immunogenic "heat tumors", thereby activating acquired immunity
to a certain extent.
Strategies to activate innate immunity and cascade to initiate acquired immunity can enhance the effectiveness of anti-tumor immunotherapy and avoid the effects of
individual differences.
Interferon gene stimulating factor (STING) is considered an important target for
activating innate immunity.
Simply put, damaged double-stranded DNA (dsDNA) in the cytoplasm is captured and then catalyzed by cyclic GMP-AMP synthetase (cGAS) to form loops [G(2',5')pA(3',5')p] (cGAMP).

cGAMP, also known as cyclic dinucleotides (CDNs), further activates STING, inducing the production of type I interferons (IFNs), which are essential for
activating acquired immunity.
Currently, the main strategy of STING-targeted therapy is the administration of the STING agonist CDN, which is a dose-dependent approach
.
However, too much CDN can cause serious side effects and promote the up-regulation of PD-L1, thereby increasing tumor-regulatory T cell infiltration and reducing the efficiency
of anti-tumor immunity.
In recent years, researchers have combined other treatments to enhance the activation efficiency of STING signaling to achieve a more efficient anti-tumor immune response, thereby circumventing immunosuppression
caused by excessive CDN.
In STING signaling, cytoplasmic dsDNA is the first initiator.

Theoretically, all effective ways to leak dsDNA into the cytoplasm can initiate STING signaling
.
For example, delivering the chemotherapy drug doxorubicin to the nucleus can lead to the release of nuclear DNA, which activates STING signaling
.
However, the side effects are relatively uncontrollable
.
Under controlled irradiation, photodynamic therapy (PDT) produces a short-range action of reactive oxygen species (ROS) with limited side effects, which can disrupt the redox balance of cells, causing dsDNA leakage in mitochondria and even nuclei, thereby activating STING signaling
.
Diagram of mechanistic patterns (image from ACS Nano) Metal ions have an amazing role
in immunomodulation.
For example, Mn²⁺ can enhance the STING signal
.
Overall,^Mn2+ can amplify the STING signal
by enhancing cGAS catalytic activity, STING activity, and cGAMP-STING affinity.
In order to avoid the toxicity of free Mn2+, degradable nanomaterials such as amorphous manganese phosphate or manganese dioxide were selected to provide^Mn2+
.
In this study, in order to amplify STING signals to enhance innate immunity, simple M@P@HA nanoparticles were constructed as STING amplifiers
.
First, the PDT reagent protoporphyrin (PpIX) was loaded into hollow manganese dioxide (H-MnO2), and then the CD44-targeting molecule hyaluronic acid (HA)
was modified on the surface of the nanosystem by layer upon layer self-assembly.
Simply put, M@P@HA target tumor cells
through overexpressed CD44 receptors.
Under the action of intracellular glutathione (GSH), M@P@HA decomposes with the release of^Mn2+ and PpIX, and the photoactivity of PpIX is restored
.
Under light irradiation, there is a considerable amount of ROS that can effectively destroy mitochondria, which are most sensitive to redox pressure, thus causing cytoplasmic dsDNA leakage and triggering STING signals
.
Since damaged mitochondrial dsDNA is easily released and captured by tumor-associated macrophages (TAMs, type M2), the STING signal of the TAM is also activated, and the TAMs are polarized into anti-tumor M1 macrophages, thereby enhancing innate immunity
.
In animal experiments, it has been found that whether local injection or systemic injection, the nanosystem activates innate immunity by amplifying the STING signal of the tumor, and then activates T cells in cascade to improve anti-tumor efficiency
.
In conclusion, the study found that in tumors with low immunogenicity, M@P@HA by amplifying the STING signal of tumor tissue, not only can it activate innate immunity, but also activate CD8⁺T cell infiltration in cascade
.

Original link: https://pubs.
acs.
org/doi/full/10.
1021/acsnano.
2c03509

—END—

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