Intercellular 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<sup>+</sup> T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8<sup>+</sup> 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 exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8<sup>+</sup> T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.
Authors
- Andrea Raimondi (ORCID: https://orcid.org/0000-0002-4563-386X)
- Kilian Schober (ORCID: https://orcid.org/0000-0001-9323-9472)
- Brandon W. Higgs (ORCID: https://orcid.org/0000-0002-2951-0245)
- Christoph Heuser (ORCID: https://orcid.org/0000-0003-1410-7573)
- Zacharias Kontarakis (ORCID: https://orcid.org/0000-0001-8825-8513)
- Roland Christian Schelker (ORCID: https://orcid.org/0000-0002-3466-5866)
- Nisha Rana (ORCID: https://orcid.org/0000-0002-2216-399X)
- Luca Gattinoni (ORCID: https://orcid.org/0000-0003-2239-3282)
- Markus Barden (ORCID: https://orcid.org/0000-0002-4923-2254)
- Maria Xydia (ORCID: https://orcid.org/0000-0001-6057-5330)
- Azucena Martín-Santos
- Inmaculada Hernandez-Lopez
- Jessica Fioravanti (ORCID: https://orcid.org/0000-0001-6263-4306)
- Donato Inverso (ORCID: https://orcid.org/0000-0003-0987-3345)
- Michael Rehli (ORCID: https://orcid.org/0000-0003-3992-932X)
- Philip Z. Brohawn (ORCID: https://orcid.org/0000-0002-7413-6539)
- William G. Telford (ORCID: https://orcid.org/0009-0002-2689-9600)
- Nicholas Strieder (ORCID: https://orcid.org/0000-0003-1183-1099)
- Philipp Beckhove (ORCID: https://orcid.org/0000-0002-0099-5576)
- Matteo Iannacone (ORCID: https://orcid.org/0000-0002-9370-2671)
- Tanmoy Saha (ORCID: https://orcid.org/0000-0003-3408-4188)
- Jeremy Baldwin (ORCID: https://orcid.org/0000-0002-0367-8939)
- Claudia Gebhard (ORCID: https://orcid.org/0000-0002-5459-8381)
- Dragana Slavkovic‐Lukic (ORCID: https://orcid.org/0000-0002-3107-7727)
- Shiladitya Sengupta (ORCID: https://orcid.org/0000-0002-8065-5052)
- Fabio Mastrogiovanni
- Sina Frischholz
- Veena Kapoor
- Sanjivan Gautam
- Jacob E. Corn
Institutions
- National Institutes of Health (US)
- Vita-Salute San Raffaele University (IT)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Zurich (CH)
- Genmab (United States) (US)
- University Hospital Regensburg (DE)
- Leibniz Association (DE)
- ETH Zurich (CH)
- Universitätsklinikum Erlangen (DE)
- Harvard–MIT Division of Health Sciences and Technology (US)
- AstraZeneca (Japan) (JP)
- AstraZeneca (Finland) (FI)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Leibniz Institute for Immunotherapy
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- University of Regensburg (DE)
Publication Details
- Journal
- Cell
- Published
- 2024-09-13
- DOI
- https://doi.org/10.1016/j.cell.2024.08.029
- Citations
- 162
- Primary Topic
- Graphene and Nanomaterials Applications
- Type
- article
- Field-Weighted Citation Impact
- 29.88
Funders
- Cancer Research Institute
- Gilead Sciences
- Joachim Herz Stiftung
- US-UK Fulbright Commission
- European Commission
- Fulbright Australia
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Else Kröner-Fresenius-Stiftung
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Kinghorn Foundation
- National Institutes of Health
- European Research Council
- Leibniz-Gemeinschaft
- National Cancer Institute
- HORIZON EUROPE European Innovation Council