NMN Rejuvenates CAR-T Cells for Better Immunotherapy

Cancer immunotherapy, particularly chimeric antigen receptor (CAR-T) cell therapy, has revolutionised treatment for many blood cancers. Yet, age-related declines in cellular energy metabolism pose a significant hurdle—older patients’ CAR-T cells often exhibit mitochondrial dysfunction and reduced persistence. A recent study in Nature Cancer demonstrates that supplementing aged CAR-T cells with nicotinamide mononucleotide (NMN), a key NAD⁺ precursor, can restore their bioenergetic health and stem-like characteristics, ultimately improving anti-tumour efficacy in preclinical models (Carrasco Hope et al., 2025).

Mechanistic Insights: How NMN Rejuvenates Aged T Cells

Restoring NAD⁺ Pools:
NMN serves as an immediate precursor to NAD⁺, the central cofactor in oxidation-reduction reactions and sirtuin-mediated deacetylation. In aged CAR-T cells, NAD⁺ levels plummet, impairing mitochondrial enzymes that govern energy production and cellular repair processes. Ex vivo treatment with NMN elevated intracellular NAD⁺, reviving the activity of SIRT1 and other deacetylases that enhance mitochondrial biogenesis and autophagy (Carrasco Hope et al., 2025).

Enhancing Mitochondrial Fitness:
Age-associated mitochondrial fragmentation and decreased spare respiratory capacity limit CAR-T cell longevity. The study showed that NMN-treated aged cells displayed increased mitochondrial mass, more fused networks, and a restored spare respiratory capacity—key indicators of robust energy reserves necessary for sustained anti-tumour activity.

Boosting Stem-Like Phenotype:
Stem-like CAR-T cells, marked by CD62L and TCF1 expression, are essential for long-term tumour surveillance. NMN supplementation partially reversed the decline in these markers, shifting aged CAR-T populations toward a youthful, less-exhausted phenotype with enhanced proliferative potential.

Translational Implications

Preclinical Efficacy:
In mouse models bearing HER2-positive tumours, aged CAR-T cells pre-treated with NMN achieved tumour regression rates comparable to those of young donor cells. This suggests NMN’s capacity to equalise age disparities in CAR-T performance, widening eligibility for older patients.

Synergy with CD38 Inhibition:
The study also explored combining NMN with 78c, a selective CD38 inhibitor. CD38 consumes NAD⁺, and its age-related overexpression exacerbates NAD⁺ depletion. Dual treatment further amplified mitochondrial restoration and in vivo tumour control, indicating a promising combinatorial approach.

Towards Clinical Translation:
While human trials are pending, these findings chart a clear path: incorporating NMN into CAR-T manufacturing protocols could bolster cell fitness before infusion. Such an approach may enhance response rates, particularly in older adults who traditionally exhibit poorer outcomes.

Conclusion

This pioneering research underscores NMN’s potential beyond general wellness, positioning it as a transformative adjunct in next-generation immunotherapies. By replenishing NAD⁺, NMN revitalises aged CAR-T cells—improving mitochondrial health, reinstating stem-like qualities, and boosting tumour-killing capacity.

For those seeking to support cellular energy and resilience, consider adding Nurix’s high-purity NMN to your regimen.

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