An engineered linear cap-independent mRNA vaccine with intrinsic adjuvanticity induces potent anti-tumor immunity in mice

  • Nat Commun. 2026 Feb 26;17(1):3205. doi: 10.1038/s41467-026-69972-2.
Hongwu Yu  #  1  2 ,  Yu Yang  #  1  2 ,  Peng Lin  1  2 ,  Chengye Liu  1  2 ,  Yifan Wen  1  2 ,  Zihan Huang  1  2 ,  Zhuting Fang  3 ,  Zhixiang Hu  4  5 ,  Shenglin Huang  6  7  8
Affiliations
  • 1. Department of Integrative Oncology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Department of Oncology and Vascular Interventional Therapy, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital (Fujian Branch of Fudan University Shanghai Cancer Center), Fuzhou, China. [email protected].
  • 4. Department of Integrative Oncology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 5. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 6. Department of Integrative Oncology, Fudan University Shanghai Cancer Center, and Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Fudan University, Shanghai, China. [email protected].
  • 7. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 8. State Key Laboratory of Genetics and Development of Complex Phenotypes, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41748617 DOI: 10.1038/s41467-026-69972-2
Abstract

mRNA Cancer vaccines demonstrate potential in clinical trials, but existing platforms struggle to boost antitumor efficacy without added cost or complexity. Here, we present a streamlined linear cap-independent mRNA (LciRNA) Cancer vaccine platform, achieved by fusing a UPA protective sequence, composed of a viral exoribonuclease-resistant RNA (xrRNA) and a poly(A) binding protein (PABP) motif, to an optimized Enterovirus A internal ribosome entry site. UPA impedes exonuclease-mediated decay and recruits RNA-binding proteins to stabilize LciRNA, enabling stable in vivo expression without 5' capping or modifications. Moreover, LciRNA innately stimulates immune responses by engaging pattern-recognition receptors, promoting dendritic cell maturation, and upregulating proinflammatory signals. In murine melanoma and HPV-associated tumor models, this vaccine platform elicits strong systemic and intra-tumoral T cell responses, achieving superior tumor control, demonstrating how immune stimulation-translation synergy underpins its efficacy. Thus, we present a cost-effective platform with enhanced efficacy, and highlight coupled immune stimulation and translation as a paradigm for future mRNA Cancer vaccines.

Products