biostudies-literatureBaldwin JGJoachim Herz FoundationGerman Research FoundationMinistry of HealthElse Kroner-Fresenius FoundationNational Institutes of HealthCancer Research InstituteEuropean Innovation CouncilEuropean Research CouncilFederal Ministry of Education and Research Bonn OfficeFondazione AIRC per la ricerca sul cancro ETSNational Cancer InstituteNCI NIH HHSAustralian American Educational Foundation6614-6630.e21https://www.ebi.ac.uk/biostudies/studies/S-EPMC11623344biostudies-literatureUnknown187(23)Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8⁺ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8⁺ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibCellIntercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.PMC11623344957502R01 CA135242R01 CA293908725038R01 CA276525Inverso DRaimondi AHiggs BWRana NGebhard CTelford WGBaldwin JGIannacone MMastrogiovanni FRehli MSengupta SGautam SSlavkovic-Lukic DStrieder NBarden MMartin-Santos AFrischholz SGattinoni LSchober KFioravanti JKapoor VKontarakis ZSaha TSchelker RCCorn JEBeckhove PXydia MBrohawn PHeuser-Loy CHernandez-Lopez IfalseIntercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8⁺ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8⁺ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhib2024-01-01T00:00:00Z2024 Nov2026-06-06T16:03:35.029Z2026-06-02T03:11:38.656ZS-EPMC116233443927677410.1016/j.cell.2024.08.029