2. Academic Validation
  3. Metal-phenolic networks reverse the immunosuppressive tumor microenvironment via dual metabolism regulation and immunogenic cell death

Metal-phenolic networks reverse the immunosuppressive tumor microenvironment via dual metabolism regulation and immunogenic cell death

  • J Control Release. 2025 Jul 10:383:113775. doi: 10.1016/j.jconrel.2025.113775.
Hoyeon Nam 1,  Heewon Park 1,  Mi Kwon Son 2,  In Kang 3,  Yuri Choi 1,  Susam Lee 1,  Sejin Kim 1,  Seungcheol Kim 1,  Hyunwoo Kim 4,  Jae-Byum Chang 4,  Yong-Kyu Lee 5,  Yeu-Chun Kim 6
Affiliations

Affiliations

  • 1 Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 2 4D Convergence Technology Institute (National Key Technology Institute in University), Korea National University of Transportation, Jeungpyeong, 27909, Republic of Korea.
  • 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 4 Department of Materials Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
  • 5 4D Convergence Technology Institute (National Key Technology Institute in University), Korea National University of Transportation, Jeungpyeong, 27909, Republic of Korea; Department of Chemical and Biological Engineering, Korea National University of Transportation, Chungju 27469, Republic of Korea. Electronic address: leeyk@ut.ac.kr.
  • 6 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: 40294797 DOI: 10.1016/j.jconrel.2025.113775
Abstract

Targeting Cancer cell metabolism has emerged as a promising strategy to reverse the immunosuppressive tumor microenvironment (TME). Aerobic glycolysis, the dominant metabolic pathway in Cancer cells, leads to glucose depletion and the accumulation of immunosuppressive metabolites such as lactate, ultimately limiting the efficacy of conventional immunotherapies. In this study, metal phenolic-networks (MPNs) are developed by coating zinc oxide (ZnO) nanoparticles with epigallocatechin gallate (EGCG) to modulate Cancer metabolism for TME reprogramming and immune activation. Under acidic conditions, MPNs release Zn2+ ions and EGCG, inhibiting both glycolysis and Mitochondrial Metabolism, effectively regulating the metabolic ability of Cancer cells. Furthermore, severe starvation stress induced by dual metabolic inhibition triggers immunogenic cell death (ICD) without the need for conventional ICD inducers. Consequently, MPN treatment reverses the immunosuppressive TME through dual metabolic regulation and ICD, which induces dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression. These findings highlight the potential of combining metabolic therapy with immunotherapy as a novel strategy to enhance antitumor immunity and overcome the limitations of current Cancer treatments.

Keywords

Cancer metabolism; Glycolysis; ICD; Immunotherapy; Metal-phenolic network; Mitochondria; TME.

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