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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
Uijoo Kim Uijoo Kim 1,2Sunkyo Hwang Sunkyo Hwang 2Seongmin Cho Seongmin Cho 2Hyeong Yun Kim Hyeong Yun Kim 1,2Hamin Ban Hamin Ban 1,2Joohee Park Joohee Park 2Jeongwon Mun Jeongwon Mun 1,2Nayoung Kim Nayoung Kim 2Ji Hun Suh Ji Hun Suh 2Yungyeong Shin Yungyeong Shin 2Sang Bum Kim Sang Bum Kim 3Ina Yoon Ina Yoon 1Sunghoon Kim Sunghoon Kim 2,4,5*
  • 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

The final, formatted version of the article will be published soon.

    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

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.