Metabolism Holds the Key to Stronger CAR T Cell Therapies, Review Argues

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of certain blood cancers, delivering remarkable remissions in patients who had exhausted every other option. Yet the technology still falls short in many cases, particularly against solid tumours, where engineered cells often fade quickly or are silenced by a hostile tumour environment. A new review published in Nature Reviews Cancer by Jessica Morgan, Sarah MacPherson and Julian J. Lum of the Trev and Joyce Deeley Research Centre and BC Cancer Research Institute argues that the missing ingredient may be metabolism. The authors synthesize a large body of evidence showing that the metabolic state of CAR T cells, shaped at every stage from receptor design through manufacturing to the patient’s own diet, is a decisive determinant of whether these living drugs survive, persist and kill tumours effectively.

At the heart of the argument is a well-established biological principle: T cells rewire their metabolism as they activate, proliferate and differentiate. Activated T cells ramp up glycolysis, the process of breaking down glucose for rapid energy and biosynthetic building blocks, a phenomenon first described in leukocytes decades ago. But different metabolic programs produce different T cell fates. Cells burning glucose ferociously tend to become short-lived effector cells, while those relying on mitochondrial respiration and fatty acid oxidation acquire memory-like properties associated with long-term persistence. For a therapy whose success depends on engineered cells remaining alive and functional in the body for weeks or months, steering that metabolic balance is not a side detail. It is central to the therapeutic outcome.

The review highlights that the choice of co-stimulatory domain inside the CAR construct, the molecular module that signals alongside antigen recognition, fundamentally dictates these metabolic fates. The landmark comparison comes from CD28 versus 4-1BB. CAR T cells carrying CD28 signalling drive glycolysis and rapid effector function but tend to exhaust faster, whereas 4-1BB signalling promotes mitochondrial biogenesis and respiratory capacity, supporting memory development and durable persistence. A 2025 study in Cell Reports confirmed that these distinct metabolic profiles are measurable in patients treated with the approved products axicabtagene ciloleucel and tisagenlecleucel, extending earlier preclinical findings into the clinical setting. In other words, the engineering decision made on a laboratory bench years before infusion leaves a metabolic fingerprint detectable in the bloodstream of treated patients.

Beyond the classic CD28 and 4-1BB dichotomy, the authors survey a growing family of tumour necrosis factor receptor co-stimulatory domains with distinct metabolic signatures. CD27 costimulation supports metabolic fitness by enhancing de novo nucleotide and protein synthesis, and recent work shows it augments both glycolysis and the tricarboxylic acid cycle in third-generation CAR T cells, improving effector function and long-term persistence. OX40 signalling complexes with phosphoinositide 3-kinase to sustain T cell survival and proliferation, and its incorporation into CAR constructs has improved antitumour activity and in vivo persistence in lymphoma models even under repeated antigen stimulation. These findings suggest that rational selection and combination of co-stimulatory domains could be used deliberately as metabolic tuning dials, matching the engineered cell’s energy profile to the demands of a particular tumour type.

Even a perfectly designed CAR T cell, however, must contend with the tumour microenvironment, which the review describes as metabolically hostile. Tumour cells consume glucose avidly, starving infiltrating lymphocytes, while accumulating lactate, adenosine, the oncometabolite 2-hydroxyglutarate and fumarate, all of which suppress T cell function. Hypoxia and nutrient scarcity further erode mitochondrial fitness. The authors catalogue an impressive arsenal of metabolic engineering strategies designed to overcome these barriers. Overexpressing glucose transporters such as GLUT1 or GLUT3 boosts glucose uptake in nutrient-poor tumours, with a recent ‘on-demand’ GLUT3 system in glioblastoma models avoiding the exhaustion problems caused by constitutive overexpression. Engineering fructose transport via GLUT5 gives T cells access to a sugar tumours largely ignore, and a striking fungal-derived cellobiose pathway provides CAR T cells with an alternative fuel source entirely inaccessible to tumour cells. Similar logic has been applied to amino acids, with overexpression of the glutamine transporter ASCT2 enhancing BCMA-targeted CAR T cells in multiple myeloma models, and arginine metabolism engineering improving proliferation in arginine-depleted tumours.

Neutralizing inhibitory metabolites is another active frontier. Overexpression of D-2-hydroxyglutarate dehydrogenase reduces intracellular accumulation of the immunosuppressive oncometabolite and improves antitumour activity, while blocking adenosine signalling through A2A receptor antagonists or engineered adenosine-degrading enzymes protects CAR T cells from this potent immunosuppressive pathway. Even lactate, long viewed purely as a waste product that poisons T cells, is being reconsidered: inhibiting lactate dehydrogenase in combination with interleukin-21 promotes a stem-like state that improves adoptive cell therapy outcomes. Together these approaches illustrate a shift in thinking, from viewing metabolism as a passive constraint to treating it as an engineerable dimension of cell therapy design.

The review then turns to manufacturing, an underappreciated source of metabolic variability. The conditions under which CAR T cells are expanded ex vivo, including the culture medium, cytokine cocktail and expansion platform, imprint distinct metabolic and functional profiles on the final product. Studies have shown that five clinically relevant T cell expansion media activate different metabolic programs, some uncoupled from actual cellular function, and that different expansion platforms yield distinct differentiation states. Reducing ex vivo culture duration improves antileukemic activity, while human plasma-like medium better supports T cell activation. Cytokine choices matter profoundly: interleukin-7 and interleukin-15 favour memory phenotypes and superior antitumour effects compared with conventional interleukin-2, and low interleukin-2 concentrations skew expansion toward early memory cells. Yet despite this evidence, the authors emphasize that metabolic parameters in clinical manufacturing protocols remain largely unstandardized, meaning that two patients receiving nominally identical products may receive cells with substantially different metabolic fitness.

Pharmacological metabolic conditioning during manufacturing offers a further layer of control. Inhibiting PI3K or AKT signalling, or treating cells with rapamycin, can uncouple T cell expansion from differentiation, preserving stem-like, metabolically resilient phenotypes associated with better persistence. Activating the GCN2 stress pathway metabolically reprograms T cells to enhance adoptive cell therapy, while manipulating amino acid availability, including asparagine restriction and methionine regulation, tunes metabolic fitness through stress-response pathways. The authors frame these interventions as part of a continuum: the same metabolic levers available to engineers in the bioreactor are, in principle, also reachable through the patient’s own physiology after infusion.

That bridge leads to the review’s most provocative theme: host metabolism and diet. Malnutrition and cachexia are associated with poor CAR T cell therapy outcomes including survival, and body mass index shows complex associations with response in myeloma patients. Diet-based interventions are clinically accessible and scalable ways to reshape systemic metabolism before and after cell infusion. The evidence base is expanding rapidly. Dietary supplementation with beta-hydroxybutyrate, a ketone body, improved the metabolic fitness and antitumour activity of CAR T cells in mouse models of leukaemia, lymphoma and pancreatic cancer, and a clinical trial of beta-hydroxybutyrate in lymphoma patients is now registered. Very-low-carbohydrate diets have been shown to enhance human T cell immunity through immunometabolic reprogramming, and fasting-mimicking diets are safe in patients with cancer and reshape metabolism and antitumour immunity. Methionine restriction, already being tested in cancer therapy trials, intersects directly with emerging data that early methionine availability attenuates T cell exhaustion.

The authors are careful to note the double-edged nature of dietary manipulation. Ketone metabolism has been implicated in promoting pancreatic cancer progression in some contexts, and the same nutrient deprivation that stresses tumour cells can also stress the therapeutic cells themselves, making timing, duration and tumour-type specificity critical variables. Still, the overall message is one of cautious optimism. By integrating metabolic considerations across the entire therapeutic arc, from co-stimulatory domain selection and transporter engineering through standardized, metabolism-aware manufacturing to deliberate host conditioning through diet, the field may finally overcome the barriers that have kept CAR T cell therapy from fulfilling its promise in solid tumours. Metabolism, long treated as background biology, is emerging as the connective tissue linking CAR design, cell production and patient care, and the review suggests that exploiting it deliberately could unlock durable, effective CAR T cell therapy for a far broader population of patients.

Subject of Research: Metabolic regulation of CAR T cell therapy efficacy in cancer

Article Title: Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet

Article References: Morgan, J., MacPherson, S., & Lum, J. J. (2026). Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet. Nature Reviews Cancer. https://doi.org/10.1038/s41568-026-00984-2

Image Credits: AI Generated

DOI: 10.1038/s41568-026-00984-2

Keywords: CAR T cell therapy, cancer immunotherapy, immunometabolism, co-stimulatory domains, tumour microenvironment, metabolic engineering, cell manufacturing, dietary intervention, ketone bodies, solid tumours, T cell persistence, glucose metabolism