CHEMICAL SCIENCE

Novel non-IFN-I-dependent nano-STING agonists promote antitumor effects


On October 27, 2022, the team of Ralph R. Weichselbaum and Wenbin Lin of the University of Chicago published an article in the journal Nature Nanotechnology, entitled “Zinc-c-di-AMP nanoparticles target and suppress tumors via endothelial STING activation and tumor.” associated macrophage reinvigoration”。 The study uses nano-coordination polymer (NCP) to develop a novel STING stimulator, which can be administered intravenously into the whole body, destroy tumor vascular endothelial cells to achieve tumor targeting, and regulate tumor-associated macrophages to trigger strong anti-tumor effects.

The corresponding authors of the study are Professor Ralph Weichselbaum and Professor Lin Wenbin of the University of Chicago, and are strongly supported by Professor Yangxin Fu of Tsinghua University. Dr. Yang Kaiting, Dr. Han Wenbo and Jiang Xiaomin are the co-first authors of this paper.

Interferon gene stimulators (STING) are key regulatory molecules in the innate immune response that are anchored to the endoplasmic reticulum via a transmembrane structure, conformationally altered after binding to cGAMP or CDN and transported to the Golgi apparatus, and ultimately induce type I interferon (IFN-I) and other inflammatory cytokine signaling pathways by activating TANK-binding kinase 1 (TBK1)/interferon regulator 3 (IRF3) and IκB kinase (IKK)/NF-κB. Since its discovery in 2008, research on the STING pathway has rapidly expanded to the field of multiple cancer treatments and is a hot target for drug development. Although preclinical studies and clinical trials of a variety of tumors have shown attractive applications, effective systemic dosing remains a challenge. At the same time, nanomaterials are increasingly being used in drug delivery for their ability to improve drug pharmacokinetics, target tumors, and reduce side effects.

Figure 1: STING pathway and its role in cancer immunotherapy

Recently, the team of Ralph R. Weichselbaum and Lin Wenbin of the University of Chicago used nanocoordination polymer (NCP) to develop a new STING stimulator, which can be administered intravenously and systemically to destroy tumor vascular endothelial cells to achieve tumor targeting, and regulate tumor-associated macrophages to trigger strong anti-tumor effects.

NCP consists of a non-toxic zinc phosphate hydrophilic core and a lipid bilayer surrounding it consisting of polyethylene glycol (PEG) conjugated phospholipids, can be loaded with hydrophilic and hydrophobic fractions simultaneously, and can be designed to stimulate triggered drug release. ZnCDA is formed by wrapping bacterial-derived cyclic dimer adenosine monophosphate (C-di-AMP, CDA) in NCP. Intravenous ZnCDA can effectively prolong the internal circulation of CDA, and ZnCDA has advantages in preventing CDA degradation and prolonging blood circulation compared with traditional liposomal delivery of CDA. Compared with other CDN or non-CDN-type STING agonists, ZnCDA has an advantage in anti-tumor effects. In addition, ZnCDA mediates potent antitumor effects in a variety of preclinical cancer models, including subcutaneous and liver metastatic colorectal cancer (MC38), melanoma (B16F10), B-cell lymphoma (BL3750), Lewis lung cancer (LLC), and spontaneous prostate cancer transgenic (TRAMP) models. In addition, the activation of STING in tumor vascular endothelial cells amplifies the high-osmotic long retention effect (EPR), which further promotes the accumulation of ZnCDA in tumor tissues. Thus, ZnCDA’s specific disruption of the tumor vascular system may be applied to the targeted delivery of tumors with other drugs.

In this study, the authors unexpectedly found that type I interferon (IFN-I) is not required for ZnCDA’s anti-tumor effects. ZnCDA showed strong anti-tumor effects by blocking the signaling pathway with anti-IFNAR1 antibodies, using Ifnar1 and Irf3 gene defective mice, and using IFNAR1-deficient tumor cells, indicating that the anti-tumor effect of ZnCDA is not dependent on IFN-I. In addition, the authors found that in the tumor immune microenvironment, ZnCDA preferentially targets tumor-associated macrophages (TAMs), and reveals through RNA-seq that ZnCDA causes downregulation of genes related to the enzymatic process of TAM lysosomes, which regulates the antigen processing and presentation of TAM. After ZnCDA administration, antigen degradation in WT and Ifnar1-/- bone marrow-derived macrophages (BMDMs) is delayed, antigen presentation ability is enhanced, and ZnCDA induces an effective T cell response independent of IFN-I. A recent report from Immunity also showed that upregulation of genes associated with antigen presentation in BMDM was not related to IFN-I after STING activation. Further deletion of TAM or specific knockout of STING of monocytes can eliminate the anti-tumor ability of ZnCDA, thereby demonstrating that ZnCDA targets tumor-associated macrophages to regulate their antigen processing/presentation and trigger a potent anti-tumor immune response.

Figure 2: ZnCDA working model diagram

Finally, the authors used two immunological “cold” tumor models representing refractory human cancers, pancreatic cancer and glioma in situ models to validate the combined therapeutic effect of ZnCDA with immune checkpoint blockers, as well as radiotherapy. In summary, the nanodrug ZnCDA developed by the institute can enhance drug delivery and sensitize “cold” tumors, which is an effective immunomodulator and provides a new therapeutic strategy for clinically refractory tumors. (Source: Web of Science)

Related Paper Information:https://doi.org/10.1038/s41565-022-01225-x



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