Nature Sub-Journal Luo Zhong/Li Menghuan of Chongqing University develops new nano-agonists that enhance the T-cell-mediated anti-tumor immune response

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The cGAS-STING pathway is a key DNA sensing mechanism and a promising target for overcoming immune resistance to solid tumors
.
On September 28, 2022, Chongqing University Luo Zhong and Li Menghuan published a research paper entitled "A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses" at Nature Communications, which reports a bovine-based serum albumin (BSA)/ A nanoagonist of ferritin, which combines manganese (II) ions and β-lapachone, it synergistically activates cGAS-STING signaling in dendritic cells (DCs), triggering powerful adaptive anti-tumor immunity
.
In summary, cGAS-STING nanoagonists enhance tumor-specific T cell-mediated immune responses against solid tumors with poor immunogenicity in vivo, providing a powerful approach
to clinical immunotherapy.
Immunotherapy, a promising anti-tumor modality that has attracted great interest in recent years, refers to a broad class
of treatments that can stimulate the endogenous immune system to trigger anti-tumor effects.
From a mechanistic point of view, the efficacy of immunotherapy depends primarily on the mobilization of tumor-specific effector T cells, during which naïve CD4+ T and CD8⁺ T cells are activated
by interacting with antigen-bound class II and class I major histocompatibility complexes.
MHC-II and MHC-I are expressed on antigen-presenting cells (APCs
).
However, to date, the application of immunotherapy in the treatment of solid tumors has been challenging because solid tumors can coordinate highly immunosuppressed states in the microenvironment to evade T cell-mediated immune elimination
.
Specifically, tumor cells can severely interfere with the antigen presentation process by inhibiting the maturation and activation of dendritic cells (DCs), the most effective specialty APCs
in humans.
The resulting DC dysfunction will lead to severe failure of T cell initiation and ultimately to immune tolerance
.
Therefore, restoring and stimulating DC function has become a promising strategy
for revitalizing T cell-mediated anti-tumor immunity.
The cyclic guanosine phosphate-adenosine phosphate synthase (cGAS)-interferon gene (STING) signaling stimulus is an evolutionarily conserved DNA sensing mechanism in the human body that plays a key role in regulating crosstalk between tumor cells and environmental immune cells, presenting as a promising target to improve the effectiveness
of immunotherapy on solid tumors.
Manganese is an essential trace element of the human body, and its toxicology has been widely known, and a variety of oral manganese supplements have long been approved to prevent or treat diseases
associated with manganese deficiency.
From a mechanistic point of view,^Mn2+ can bind directly to cGAS to enhance its dsDNA sensitivity and cGAMP-producing enzyme activity, thereby stimulating downstream STING signaling even at low levels of tumor-derived dsDNA
.
On the other hand, Mn²⁺-cGAMP complexation can significantly enhance cGAMP's STING binding affinity to promote STING activation, which is two orders of magnitude
higher than the original cGAMP.
The study reported a bovine serum albumin (BSA)/ferritin-based nanoagonist that combines manganese(II) ions and β-lapachone, which synergistically activates cGAS-STING signaling in dendritic cells (DCs) to trigger strong adaptive anti-tumor immunity
.
Mn2+ - Anchors mannose-modified BSA and β-lapachone-backed ferritin crosslinking to provide a bioreactive protein nanoassembly that dissociates into monodispersed protein units in the acidic perivascular tumor microenvironment (TME), thereby enhancing tumor penetration and spatiotemporal control of^Mn2+ and β-lapachone to DCs and tumor cells
, respectively 。 β-lapachone causes apoptosis of immunogenic tumor cells and releases large amounts of dsDNA into TME, while^Mn2+ enhances cGAS sensitivity to dsDNA and enhances STING signaling to trigger downstream immune stimulation signals
。 On-demand activation of protein-based nanoassemblies in TME enhances the immune response of poorly immunogenic solid tumors (Figure from Nature Communications) In summary, these functions of the protein-based cGAS-STING nanoagonists in this study can work synergistically to enhance the cross-activation of DC-mediated anti-tumor effector T cells in TME and to improve the anti-tumor immune response in a low-immunogenic tumor model, Thus providing a new opportunity
to clinically enhance the efficacy of immunotherapy for solid tumor indications.

Informational message: https://doi.
org/10.
1038/s41467-022-33301-0

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