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

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.