mRNA lipid-nanoparticle-mediated mitochondrial apoptosis augments adoptive T cell immunotherapy

  • Cell Rep Med. 2026 Apr 21;7(4):102706. doi: 10.1016/j.xcrm.2026.102706.
Jiayan Fu  1 ,  Yaoqi Liu  1 ,  Zhenyu Zhong  2 ,  Benyuan Cao  1 ,  Luna Ran  1 ,  Zijia Guo  1 ,  Haiyang Dong  1 ,  Nengcheng Bao  1 ,  Rongqing Pan  3 ,  Jinqiang Wang  4 ,  Yuanhui Mao  5 ,  Yongfeng Jin  6
Affiliations
  • 1. National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China; MOE Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 2. MOE Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 3. Institute of Immunology, Bone Marrow Transplantation Center of The First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
  • 4. National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China.
  • 5. Department of Urology of The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University, Hangzhou, China. Electronic address: [email protected].
  • 6. National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China; MOE Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, China; Emergency and Trauma Centre, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China. Electronic address: [email protected].
PMID: 41916290 DOI: 10.1016/j.xcrm.2026.102706
Abstract

Adoptive T cell therapy (ACT) holds promise for Cancer Immunotherapy, yet its clinical efficacy against solid tumors remains suboptimal. An emerging strategy aims to enhance ACT by modulating mitochondrial Apoptosis (mtApoptosis) priming of Cancer cells. This study develops an mRNA-based combinational strategy that utilizes mRNA lipid nanoparticles encoding BH3 domains from activator-type proteins to trigger robust mtApoptosis, thereby augmenting antitumor immunity with ACT. This approach preferentially induces immunogenic cell death in Cancer cells and remodels the immunosuppressive microenvironment. Combined with ACT, the formulation synergistically enhances tumor cell killing in vitro by lowering the apoptotic threshold. In vivo, the combination improves therapeutic efficacy by boosting endogenous T cell cytotoxicity and mitigating ACT-induced T cell dysfunction. Single-cell transcriptomics further reveals that the combination reprograms effector T cells toward memory-like states with expanded TCR diversity. Collectively, this study proposes a combinatorial mRNA-based strategy and provides mechanistic insights for augmenting ACT through mtApoptosis priming.

Keywords
adoptive T cell therapy; mitochondrial apoptosis; solid tumor; synergistic effect; therapeutic mRNA.
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