2. Academic Validation
  3. GPC3-based circular RNA vaccine suppresses hepatocellular carcinoma progression by activating adaptive immune responses

GPC3-based circular RNA vaccine suppresses hepatocellular carcinoma progression by activating adaptive immune responses

  • Hepatology. 2025 Nov 7. doi: 10.1097/HEP.0000000000001605.
Yifan Jiang 1 2 3 4,  Yu Li 1 2 3 4,  Tong Wu 1 2 3,  Linping Cao 1,  Guangming Xu 1 2 3,  Jiwei Liu 5,  Chenguang Hua 1 2 3,  Chaofeng Ding 1,  Beng Yang 1,  Rongliang Tong 1 2,  Diyu Chen 6,  Jian Wu 1 2 3 4
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou, P.R. China.
  • 2 NHC Key Laboratory of Combined Multi-organ Transplantation, Zhejiang Province, Hangzhou, P.R. China.
  • 3 Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Zhejiang Province, Hangzhou, P.R. China.
  • 4 Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou, P.R. China.
  • 5 Zhejiang Key Laboratory of Smart Biomaterials, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
  • 6 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, P.R. China.
PMID: 41201153 DOI: 10.1097/HEP.0000000000001605
Abstract

Background and aims: Messenger RNA (mRNA) vaccine is a promising approach for Cancer therapy. However, the development of mRNA Cancer vaccines encounters several challenges, including mRNA instability, inefficient delivery systems, and potential biosafety concerns. Addressing these issues requires optimizing mRNA design, developing novel delivery vectors, and enhancing immune responses. We aimed to develop a circular RNA (circRNA)-based Cancer vaccine targeting tumor-associated antigen Glypican-3 (GPC3), a promising target in hepatocellular carcinoma (HCC), to improve antigen stability and anti-tumor immune responses.

Approach and results: We designed a circRNA-based vaccine encoding GPC3 for HCC and evaluated the therapeutic efficacy and safety of the circGPC3 vaccine. The circGPC3 vaccine demonstrated sustained antigen production, overcoming the inherent limitations of traditional mRNA vaccines and resulting in more potent and durable anti-tumor immune responses. In addition, we incorporated a Toll-like Receptor 4 (TLR4) agonist as an Adjuvant to further enhance immune responses. CircGPC3 vaccine plus TLR4 Agonist effectively suppressed tumor progression in HCC. We employed multiplex immunofluorescence, single-cell Sequencing, spatial transcriptomics, and mass cytometry to characterize the tumor microenvironment (TME) in mice following combination therapy and to elucidate the mechanism. Mechanistically, the circGPC3 vaccine significantly enhanced immunoproteasome-mediated antigen presentation and strengthened the interaction between cDC1 and CD8 + T cells through the MHC-I pathway, therefore facilitating a more effective initiation of adaptive immune responses and reprogramming TME.

Conclusions: The circGPC3 Cancer vaccine demonstrated superior efficacy compared with the mRNA Cancer vaccine. When further combined with a TLR4 Agonist, it disrupted immune tolerance in HCC, offering a promising translational treatment strategy for HCC.

Keywords

Glypican-3; cancer immunotherapy; cancer vaccine; circular RNA; messenger RNA.

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