The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma

Li, Kesang; Ye, Yingyi; Liu, Liqin; Sha, Qian; Wang, Xiaolu; Jiao, Ting; Zhang, Li; Wang, Jinyan

doi:10.1039/d0bm00870b

Cited by 29 publications

(28 citation statements)

References 26 publications

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“…Therapeutic benefits of targeting STING pathway have been demonstrated in preclinical murine tumor models. [ 6–9 ] Several clinical trials are ongoing to assess the antitumor efficacy of STING agonists in mono‐ or combination therapies. [ 10 ]…”

Section: Introductionmentioning

confidence: 99%

“…Therapeutic benefits of targeting STING pathway have been demonstrated in preclinical murine tumor models. [6][7][8][9] Several clinical trials are ongoing to assess the antitumor efficacy of STING agonists in mono-or combination therapies. [10] Cyclic dinucleotides (CDNs) are natural STING agonists but the clinical application of CDNs as immunotherapeutics remains a significant challenge.…”

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: Introductionmentioning

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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“…The newly discovered stimulator of interferon genes (STING), a transmembrane complex located in the endoplasmic reticulum, has opened a new avenue for enhancing the functions of APCs. − It has demonstrated that STING activation can stimulate the production of type I interferons (IFNs) via interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-κB) signaling pathways, which can induce the activation of APCs. , Activated APCs indirectly enable the activation and expansion of CD8 + T cells through the interaction between CD4 + T cells and APCs, or can directly activate CD8 + T cells. − In addition, type I IFNs can act directly on CD4 + T cells and CD8 + T cells to allow clonal expansion. , Multiple studies have reported that intratumoral injection of the STING agonist (cyclic guanosine monophosphate–adenosine monophosphate, cGAMP) was able to reverse tumor immunosuppression and elicit tumor-specific CD8 + T cells. − Therefore, the STING agonist-cGAMP is a potential agent for overcoming the poor immunogenicity of tumor cells and enhancing the functions of APCs. , However, cGAMP is a cyclic di-nucleotide linked by two phosphodiester bonds. Similar to other nucleic acids, it is easy to be degraded by extracellular phosphodiesterase and can hardly cross plasma membrane to enter the cytoplasm. − Several recently published studies have demonstrated that nanoparticles could improve the in vivo delivery efficiency of cGAMP, ,,− but no co-delivery of cGAMP and siRNA into APCs has been reported.…”

Section: Introductionmentioning

confidence: 99%

Co-delivery of Phagocytosis Checkpoint Silencer and Stimulator of Interferon Genes Agonist for Synergetic Cancer Immunotherapy

Chen

Shen

et al. 2021

ACS Appl. Mater. Interfaces

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Efficient capture and presentation of tumor antigens by antigen-presenting cells (APCs), especially dendritic cells (DCs), are crucial for activating the anti-tumor immunity. However, APCs are immunosuppressed in the tumor microenvironment, which hinders the tumor elimination. To reprogram APCs for inducing strong anti-tumor immunity, we report here a co-delivery immunotherapeutic strategy targeting the phagocytosis checkpoint (signal regulatory protein α, SIRPα) and stimulator of interferon genes (STING) of APCs to jointly enhance their ability of capturing and presenting tumor antigens. In brief, a small interfering RNA targeting SIRPα (siSIRPα) and a STING agonist (cGAMP) were co-delivered into APCs by the encapsulation into poly(ethylene glycol)-b-poly(lactide-co-glycolide)-based polymeric nanoparticles (NPsiSIRPα/cGAMP). siSIRPα-mediated SIRPα silence promoted APCs to actively capture tumor antigens by engulfing tumor cells. The cGAMP-stimulated STING signaling pathway further enhanced the functions of APCs, thereby increased the activation and expansion of CD8+ T cells. Using ovalbumin (OVA)-expressing melanoma as a model, we demonstrated that NPsiSIRPα/cGAMP stimulated the activation of OVA-specific CD8+ T cells and induced holistic anti-tumor immune responses by reversing the immunosuppressive phenotype of APCs. Collectively, this co-delivery strategy synergistically enhanced the functions of APCs and can be extended to the treatment of tumors with poor immunogenicity.

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“…Compared with no treatment or treatment with immune-checkpoint inhibitors alone, the co-administration of STING agonists with CTLA4 and PD1 antibodies in a preclinical HPV + oral tumor model displayed the most significant survival advantage ( 106 ). Moreover, in B16F10- and BRAF-mutated murine models, the group treated with cGAMP encapsulated into lipid nanoparticles conjugated with mannose (LP-cGAMP) and anti-programmed death-ligand 1 (PD-L1) exhibited a more long-lasting inhibition of tumor growth and achieved a more prolonged survival than others ( 107 ).…”

Section: Sting Agonists In Cancer Therapymentioning

confidence: 99%

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

Gan

Han

et al. 2022

Front. Immunol.

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As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

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The lipid platform increases the activity of STING agonists to synergize checkpoint blockade therapy against melanoma

Abstract: Although selective BRAF inhibitors are current frontline therapeutics in BRAF mutated melanoma, their efficacy is limited by drug resistance. Novel strategies with long-lasting anti-tumor effect are urgently sought after. Activation...

Cited by 29 publications

References 26 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

Co-delivery of Phagocytosis Checkpoint Silencer and Stimulator of Interferon Genes Agonist for Synergetic Cancer Immunotherapy

The cGAS/STING Pathway: A Novel Target for Cancer Therapy

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