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Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancr...

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Autores principales: Liu, Wei, Alameh, Mohamad-Gabriel, Yang, June F., Xu, Jonathan R., Lin, Paulo J. C., Tam, Ying K., Weissman, Drew, You, Jianxin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739380/
https://www.ncbi.nlm.nih.gov/pubmed/36498833
http://dx.doi.org/10.3390/ijms232314504
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author Liu, Wei
Alameh, Mohamad-Gabriel
Yang, June F.
Xu, Jonathan R.
Lin, Paulo J. C.
Tam, Ying K.
Weissman, Drew
You, Jianxin
author_facet Liu, Wei
Alameh, Mohamad-Gabriel
Yang, June F.
Xu, Jonathan R.
Lin, Paulo J. C.
Tam, Ying K.
Weissman, Drew
You, Jianxin
author_sort Liu, Wei
collection PubMed
description Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STING(R284S) into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STING(R284S) mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STING(R284S) can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically “cold” tumors that are refractory to current therapies.
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spelling pubmed-97393802022-12-11 Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity Liu, Wei Alameh, Mohamad-Gabriel Yang, June F. Xu, Jonathan R. Lin, Paulo J. C. Tam, Ying K. Weissman, Drew You, Jianxin Int J Mol Sci Article Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically “cold” tumor microenvironment (TME). However, we have shown that STING is silenced in many human cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC). In this study, we demonstrated that mRNA-lipid nanoparticle (LNP) technology could be used to efficiently deliver naturally occurring constitutively active STING mutant STING(R284S) into these cancer cells to reactivate STING antitumor immunity and trigger robust killing of tumor cells. STING agonists are being actively pursued as cancer immunotherapies. However, traditional STING agonists can induce T cell cytotoxicity, counteracting the desired antitumor immune response. In addition, the antitumor efficacy of traditional STING agonists obligatorily depends on STING expression and does not work in STING-silenced cancers. Importantly, we found that STING(R284S) mRNA-LNP does not introduce T cell cytotoxicity. Our studies demonstrated that mRNA-LNP delivery of STING(R284S) can reactivate the antitumor response without introducing antiproliferative effects in lymphocytic immune cells, overcoming the toxicity and limitations of conventional STING agonists. Our work therefore identifies a novel therapeutic tool for reactivating antitumor immunity in an array of STING-silenced immunologically “cold” tumors that are refractory to current therapies. MDPI 2022-11-22 /pmc/articles/PMC9739380/ /pubmed/36498833 http://dx.doi.org/10.3390/ijms232314504 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Wei
Alameh, Mohamad-Gabriel
Yang, June F.
Xu, Jonathan R.
Lin, Paulo J. C.
Tam, Ying K.
Weissman, Drew
You, Jianxin
Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title_full Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title_fullStr Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title_full_unstemmed Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title_short Lipid Nanoparticles Delivering Constitutively Active STING mRNA to Stimulate Antitumor Immunity
title_sort lipid nanoparticles delivering constitutively active sting mrna to stimulate antitumor immunity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9739380/
https://www.ncbi.nlm.nih.gov/pubmed/36498833
http://dx.doi.org/10.3390/ijms232314504
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