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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1454504
This article is part of the Research Topic Innate Immune Pathways as Targets for Developing Therapeutic Intervention against Human Cancers View all 5 articles
Intratumoral delivery of mRNA encoding the endogenous TLR2/6 agonist UNE-C1 induces immunogenic cell death and enhances antitumor activity
Provisionally accepted- 1 College of Pharmacy, Yonsei University, Incheon, Republic of Korea
- 2 Institute for Artificial Intelligence and Biomedical Research, Medicinal Bioconvergence Research Center, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
- 3 College of Pharmacy, Sahmyook University, Seoul, Republic of Korea
- 4 Severance Hospital, College of Medicine, Yonsei University, Seoul, Republic of Korea
- 5 Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Incheon, Republic of Korea
Recent investigations have highlighted the intratumoral administration of Toll-like receptor (TLR) ligands as a promising approach to initiate localized immune responses and enhance antitumor immunity. However, the clinical application of these ligands is limited by their rapid dissemination from the tumor microenvironment, which raises concerns about reduced effectiveness and systemic toxicity. To address these challenges, our study focused on the intratumoral delivery of mRNA encoding UNE-C1, a TLR2/6 ligand known for its efficacy and low toxicity profile. Additionally, we explored the potential of UNE-C1 to induce immunogenic cell death (ICD) through autocrine mechanisms facilitated by the release of damage-associated molecular patterns (DAMPs) triggered by TLR2 activation. Our findings indicate that sensitivity to UNE-C1-induced cell death is dependent on the expression levels of TLR2 and the Fas-associated death domain (FADD) in cancer cells. Furthermore, we investigated the paracrine activation of dendritic cells (DCs) by UNE-C1 via TLR2 signaling, which in turn primes a CD8 + T cell response essential for tumor regression. Our results advocate for the intratumoral delivery of UNE-C1 via mRNA therapy as a promising strategy for innovative antitumor treatments.
Keywords: cancer immunotherapy1, Toll-like receptor2, Intratumoral treatment3, mRNA therapeutics4, tumor microenvironment5, Immunogenic cell death6
Received: 25 Jun 2024; Accepted: 05 Nov 2024.
Copyright: © 2024 Kim, Hwang, Cho, Kim, Ban, Park, Mun, Kim, Suh, Shin, Kim, Yoon and Kim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Sunghoon Kim, Institute for Artificial Intelligence and Biomedical Research, Medicinal Bioconvergence Research Center, College of Pharmacy, Yonsei University, Incheon, Republic of Korea
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