Age-associated NAD Decline Drives CAR-T Cell Therapy Failure

CAR-T cell therapy is one of the most promising cancer treatment methods. However, various obstacles limit its application and efficacy. Among them, whether and how aging affects the therapeutic effect of CAR-T cells remains largely unclear.

On May 20, 2025, researchers from the University of Lausanne and Geneva University Hospitals published a research paper titled "Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure" in the Nature sub-journal Nature Cancer.

This study shows that aging-associated decline in nicotinamide adenine dinucleotide (NAD) levels drives CAR-T cell therapy failure, while restoring NAD levels can improve the therapeutic efficacy of aged CAR-T cells. This discovery provides a promising approach to improving CAR-T cell therapy.

Immunotherapy strategies based on CAR-T cells are currently among the most promising methods for cancer treatment. Among the characteristics determining the successful response to CAR-T cell therapy, the long-term maintenance of T cell populations with stem cell-like properties is crucial. Therefore, the CAR-T cell field is progressing towards strategies that favor increasing the quantity and quality of stem cell-like T cells in CAR-T infusion products.

Importantly, this stem cell-like population initiates a specific metabolic program that mainly depends on mitochondrial activity. In fact, recent studies have shown that CAR-T cells with impaired mitochondrial function are associated with poor therapeutic efficacy, and in preclinical models, metabolic interventions that enhance mitochondrial metabolism can improve CAR-T cell therapy outcomes.

An important metabolic molecule ensuring mitochondrial health is nicotinamide adenine dinucleotide (NAD). NAD is a well-known cofactor that plays a key role in redox balance and energy metabolism, providing energy for oxidative phosphorylation. Additionally, it serves as a substrate for various enzymes such as sirtuin deacetylases (SIRT), which regulate the expression of PPARγ coactivator-1α (PGC-1α), a transcriptional coactivator involved in mitochondrial biogenesis.

NAD metabolism plays a critical regulatory role in T cell fate and function. Therefore, changes in NAD homeostasis are associated with impaired T cell responses, and restoring mitochondrial dysfunction by increasing NAD levels has been shown to prevent exhaustion of tumor-infiltrating lymphocytes (TILs).

Aging is the primary risk factor associated with cancer. Most (about 75%) cancer patients and those eligible for cancer immunotherapy are over 65 years old. Importantly, in the context of CAR-T cell therapy, the highest response rates in B cell acute lymphoblastic leukemia (B-ALL) are observed when the median age at diagnosis is under 20 years, with response rates declining with increasing age.

However, whether aging is an important limiting factor for CAR-T cell efficacy and its underlying mechanisms remain unclear.

Previous studies have reported that aging causes immune and metabolic dysfunction, thereby altering anti-tumor responses. Interestingly, mitochondrial dysfunction is a prominent feature of aging, and NAD reduction has been described in multiple tissues including white adipose tissue (WAT), muscle, and liver.

In this new study, the research team demonstrated that age is a limiting factor for effective CAR-T cell response.

Specifically, the study showed that CAR-T cells generated from T cells of aged female mice exhibit mitochondrial dysfunction caused by NAD depletion, resulting in poor stem cell-like characteristics and impaired anti-tumor function in vivo. Moreover, human data analysis indicated that both age and NAD metabolism determine responses to CAR-T cell therapy. More importantly, by targeting the NAD pathway, the team successfully restored mitochondrial health and function in CAR-T cells derived from elderly donors.

These findings indicate that aging-associated NAD decline limits successful CAR-T cell responses, and correcting aging-induced metabolic and functional defects (such as restoring NAD homeostasis) represents a promising strategy to improve CAR-T cell therapy.