2. Academic Validation
  3. Condensate nanovaccine adjuvants augment CD8+ T-Cell-dependent antitumor immunity through mtDNA leakage-triggered cGAS-STING axis activation

Condensate nanovaccine adjuvants augment CD8+ T-Cell-dependent antitumor immunity through mtDNA leakage-triggered cGAS-STING axis activation

  • Signal Transduct Target Ther. 2025 Oct 21;10(1):349. doi: 10.1038/s41392-025-02447-w.
Yu Tang # 1,  Zhiyuan Luo # 2,  Zhanni Ma # 1,  Lingling Han # 1,  Yurong Zhou # 3,  Tianci Liang 1,  Kangsen Yang 1,  Lei Zhao 4,  Xiaoyuan Chen 5 6 7,  Pengfei Zhang 8
Affiliations

Affiliations

  • 1 Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
  • 2 Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
  • 3 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China.
  • 4 Department of Orthopedics, Air Force Hospital of Eastern Theater of PLA, Nanjing, China.
  • 5 Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, Biomedical Engineering, Clinical Imaging Research Centre, Pharmacy and Pharmaceutical Sciences, and Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, Singapore. chen.shawn@nus.edu.sg.
  • 6 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore. chen.shawn@nus.edu.sg.
  • 7 Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. chen.shawn@nus.edu.sg.
  • 8 Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China. zpf0418@i.smu.edu.cn.
  • # Contributed equally.
PMID: 41115902 DOI: 10.1038/s41392-025-02447-w
Abstract

The variety and functionality of current clinical vaccine adjuvants remain limited. Conventional aluminum-based adjuvants predominantly induce Th2-biased humoral immunity but exhibit a limited capacity to elicit Th1-mediated cellular immune responses, particularly tumor antigen-specific cytotoxic CD8+ T lymphocytes (CTLs), which are essential for effective Cancer vaccine performance. Inspired by natural biomolecular condensates, we developed a versatile noncovalent protein self-assembly strategy distinct from traditional approaches requiring structural domain modifications or bifunctional crosslinkers. Our methodology employs amphiphilic molecules (sodium myristate/SMA and sodium dodecyl thiolate/SDT) as molecular bridges to mediate protein‒protein interactions through hydrophobic forces and disulfide bond formation. This process generates nanoscale protein condensate (PCD) vaccines with exceptional stability. As a novel Adjuvant system, these synthetic condensates significantly enhance antigen cross-presentation by optimizing key parameters: antigen loading capacity, lymph node targeting, cytosolic delivery, and lysosomal escape. Consequently, they induce robust antigen-specific CTL responses and humoral immunity, demonstrating potent antitumor efficacy. Importantly, we found that the synthetic protein condensate (PCD) alone can act as a nanoadjuvant. By increasing mitochondrial membrane permeability, PCD induces mitochondrial DNA leakage into the cytosol, activating the cGAS‒STING pathway and promoting DC maturation. This safe and scalable platform eliminates the need for complex covalent modifications or genetic engineering, and it facilitates the design of diverse modular antigens, including neoantigens and viral antigens. Given its straightforward manufacturing process and superior immunogenicity, this synthetic PCD vaccine Adjuvant has significant potential for clinical application and translation.

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