2. Academic Validation
  3. Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function

Local delivery of IL-12 mRNA and indoximod prodrug potentiates antitumor immunity by increasing T cell effector function

  • J Control Release. 2025 Jun 18:385:113970. doi: 10.1016/j.jconrel.2025.113970.
Heewon Park 1,  In Kang 2,  Susam Lee 1,  Minsa Park 3,  Seungcheol Kim 4,  Su Yeon Lim 5,  Hoyeon Nam 1,  Dohyun Yun 4,  Sejin Kim 4,  Yesol Kim 4,  Ji Hoon Jeong 5,  Kyuri Lee 6,  Heung Kyu Lee 7,  Yong-Kyu Lee 8,  Yeu-Chun Kim 9
Affiliations

Affiliations

  • 1 Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju 27469, Republic of Korea; 4D Convergence Technology Institute (National Key Technology Institute in University), Korea National University of Transportation, Jeungpyeong 27909, Republic of Korea.
  • 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 3 School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul 02841, Republic of Korea.
  • 4 Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 5 School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
  • 6 School of Biosystems and Biomedical Sciences, College of Health Science, Korea University, Seoul 02841, Republic of Korea; Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02841, Republic of Korea.
  • 7 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. Electronic address: heungkyu.lee@kaist.ac.kr.
  • 8 Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju 27469, Republic of Korea; 4D Convergence Technology Institute (National Key Technology Institute in University), Korea National University of Transportation, Jeungpyeong 27909, Republic of Korea. Electronic address: leeyk@ut.ac.kr.
  • 9 Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea. Electronic address: dohnanyi@kaist.ac.kr.
PMID: 40541741 DOI: 10.1016/j.jconrel.2025.113970
Abstract

The administration of recombinant cytokines, particularly interleukin-12 (IL-12), holds promising clinical potential for treating various cancers. Sustained intratumoral delivery of IL-12 can restore tumor resident CD8+ effector T cells and induce the priming of antitumor CD8+ effector T cells. However, these CD8+ T cell-dependent Anticancer efficacy is usually transient and accompanies the activation of immune suppressive CD4+Foxp3+ T regulatory cells. The underlying mechanism of T regulatory cell activation in IL-12 therapy is the upregulation of IFNγ dependent indoleamine 2,3-dioxygenase (IDO) expression. Due to this negative feedback, the combinatorial use of drugs should be considered to enhance the efficacy of IL-12-mediated therapy. Herein, we designed a lipid nanoparticle (LNP) system which can successfully deliver an IDO Inhibitor indoximod (IND) and IL-12 encoding mRNA. In order to increase the loading efficiency, the IND prodrug was synthesized by conjugating IND with Cholesterol by ester linkage. Optimized IND prodrug encapsulating LNP successfully transfected tumor cells and macrophages, resulting in the secretion of IL-12 cytokine. With IL-12 transfection, macrophages upregulated T cell co-stimulation factor and released TNFα cytokine, indicating that the tumor microenvironment could be changed from cold tumor to hot tumor for immunotherapy. Also, by the elevated secretion of IL-12 cytokine, T cells release high levels of IFNγ, which is a central role in IL-12-mediated immunotherapy. This co-delivery system presents a promising strategy to overcome the limitations of single IL-12-mediated therapy by simultaneously promoting antitumor immune responses and inhibiting immunosuppressive mechanisms, thereby enhancing the overall efficacy of Cancer Immunotherapy.

Keywords

Cancer immunotherapy; IFNγ-IDO pathway; IL-12 mRNA; Lipid nanoparticle; Prodrug synthesis.

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