SLC25A51 mRNA-LNP Armors T Cells with Mitochondrial Fitness in Cancer Treatment.

Pancreatic ductal adenocarcinoma remains largely refractory to adoptive T-cell therapies owing to a metabolically hostile tumor microenvironment that compromises mitochondrial functions. Here, we develop an ex vivo SLC25A51 mRNA-lipid nanoparticle (mRNA-LNP) engineering strategy to reinforce mitochondrial fitness in T cells and assess its therapeutic potential in pancreatic cancer xenografts. SLC25A51 mRNA-LNPs efficiently transfected primary T cells, resulting in sustained SLC25A51 expression and marked enhancement of mitochondrial membrane potential, oxidative respiration, and ATP production. These metabolic gains translated into increased T-cell proliferation, augmented effector cytokine secretion, and improved tumor-cell killing in vitro. In a subcutaneous Pan02 model, adoptive transfer of SLC25A51-engineered T cells significantly delayed tumor progression and extended survival, accompanied by enhanced intratumoral activation and enrichment of central-memory T-cell phenotypes. Therapeutic efficacy was further amplified by Galectin-9 blockade and conferred durable protection upon tumor rechallenge. Importantly, to assess clinical relevance, we extended this approach to a Capan-2-derived peritoneal metastasis model, in which SLC25A51-armored CAR T cells achieved robust control of disseminated tumor burden and prolonged survival. This study establishes SLC25A51 mRNA-LNP engineering as a practical and modular strategy to enhance mitochondrial fitness and restore T-cell antitumor activity.