Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.
Authors
- Jesús Corría-Osorio (ORCID: https://orcid.org/0000-0001-6844-6170)
- François Kuonen (ORCID: https://orcid.org/0000-0001-6137-7483)
- Johan Auwerx (ORCID: https://orcid.org/0000-0002-5065-5393)
- Massimo Andreatta (ORCID: https://orcid.org/0000-0002-8036-2647)
- Santiago J. Carmona (ORCID: https://orcid.org/0000-0002-2495-0671)
- Patrizia D’Amelio (ORCID: https://orcid.org/0000-0002-4467-8337)
- Nicola Vannini (ORCID: https://orcid.org/0000-0002-6351-7512)
- George Coukos (ORCID: https://orcid.org/0000-0001-8813-7367)
- Christine Pich-Bavastro (ORCID: https://orcid.org/0000-0002-6526-749X)
- Yi-Hsuan Chiang (ORCID: https://orcid.org/0009-0005-0683-0149)
- Ping‐Chih Ho (ORCID: https://orcid.org/0000-0003-3078-3774)
- Jana de Sostoa (ORCID: https://orcid.org/0000-0001-8563-9273)
- Pierpaolo Ginefra
- Catherine Ronet
- Helen Carrasco Hope
- Denis Migliorini (ORCID: https://orcid.org/0000-0003-0151-3222)
Institutions
- University of Geneva (CH)
- Centre Hospitalier Universitaire Vaudois (CH)
- University Hospital of Geneva (CH)
- Ludwig Cancer Research (CH)
- Swiss Cancer Center Léman (CH)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Lausanne (CH)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s43018-025-00982-7
- Citations
- 20
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 20.91