Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal anti-tumor effect

Wang, Chao; Sun, Zhaoyi; Zhao, Chenxuan; Zhang, Zhewei; Wang, Haoran; Liu, Yang; Guo, Yunfei; Zhang, Bingtao; Gu, Lihong; Yu, Yue; Hu, Yiqiao; Wu, Jinhui

doi:10.1016/j.jconrel.2021.01.036

Cited by 80 publications

(66 citation statements)

References 44 publications

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“…To facilitate efficient tumor delivery of Mn 2+ ions, nanoparticle and hydrogel based delivery systems have been developed as recently reported in several elegant studies. [24,37,38] The MnP-PEG nanocluster described here has well characterized physicochemical properties and does not require any additional chemotherapy or radiotherapy to generate intracellular double-stranded DNA for activation of the cGAS-STING pathway, and, therefore, represents a simple yet potent nanoparticulate STING activator.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] Recently, Mn 2+ ions have been discovered to directly activate the cyclic GMP-AMP synthase (cGAS), the cytosolic DNA sensor, to synthesize 2′3′-cyclic GMP-AMP (referred as cGAMP for simplicity). [21,23] However, direct administration of Mn 2+ ion in vivo results in insufficient accumulation of Mn 2+ ions to reach an effective concentration in the tumor microenvironment [24] and the diffusion of Mn 2+ ions into other tissues, such as brain, leading to potential toxicity. [25] Here, we developed an Mn-based nanoparticulate STING agonist that could effectively activate the STING pathway in vitro and elicit robust anticancer immune responses in vivo (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Gao

Xie

Lei

et al. 2021

Advanced Therapeutics

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Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn 2+ ions have been recently discovered to directly activate the cyclic GMP-AMP (cGAMP) synthase (cGAS) and augment cGAMP-STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP-PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS-STING pathway. MnP-PEG nanoclusters activate the immature bone marrow-derived dendritic cells (DCs) leading to 57.3-and 13.3-fold higher production of interferon and interleukin-6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by DCs and acid-triggered release of Mn 2+ ions in the endolysosomes. Intratumoral administration of MnP-PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP-PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Gao

Xie

Lei

et al. 2021

Advanced Therapeutics

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“…[9] Direct intratumoral injection of Mn ions, on the other hand, is difficult to distribute effectively to APCs and can rapidly disseminate to other tissues and organs, increasing the risk of systemic damage. [10] As a result, delivery of Mn ions to APCs using nanoparticles can increase the efficiency of APC priming while minimizing side effects. [11] Nucleic acid-based immunoadjuvants can effectively induce M1 polarization of macrophages.…”

Section: Introductionmentioning

confidence: 99%

Combination of Metal‐Phenolic Network‐Based Immunoactive Nanoparticles and Bipolar Irreversible Electroporation for Effective Cancer Immunotherapy

Han

Shin

Lee

et al. 2022

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“…Compared with free Mn 2+ ions, nanoparticle modification can increase the retention time of Mn 2+ in the tumor and improve biosafety in vivo [7]. Importantly, sustained release of Mn 2+ from enable the maximization activation of STING pathway, thus leading to potent tumor killing ability [8][9][10]. Hence, it is of great significance to construct a nanoprobe with acidic response and sustained release behavior for fully exploiting the MR imaging and STING activation functions of Mn 2+ .…”

Section: Introductionmentioning

confidence: 99%

A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

Yang

et al. 2021

J Nanobiotechnol

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Background Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored. Methods and results Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models. Conclusions This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy. Graphical Abstract

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Maintaining manganese in tumor to activate cGAS-STING pathway evokes a robust abscopal anti-tumor effect

Cited by 80 publications

References 44 publications

A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Combination of Metal‐Phenolic Network‐Based Immunoactive Nanoparticles and Bipolar Irreversible Electroporation for Effective Cancer Immunotherapy

A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

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