By reengineering how engineered immune cells use glucose, fats and amino acids, researchers hope to help CAR-T therapies survive the hostile metabolism of solid tumors.
Research: Metabolic reprogramming of CAR-T cells: a multipronged strategy to overcome the immunosuppressive tumor microenvironment. Image credit: Corona Borealis Studio / Shutterstock
In a recent review published in a magazine Cell communication and signalingChinese researchers evaluated how metabolic reprogramming increases the efficacy of chimeric antigen receptor T cells (CAR-T cells) in harsh tumor environments.
CAR-T metabolism in the solid tumor setting
Why are some of the most advanced cancer treatments ineffective against solid tumors?Despite remarkable success in blood cancers, CAR-T cell therapy is less effective against solid tumors due to the tumor microenvironment. This environment deprives immune cells of nutrients and disrupts metabolic pathways, resulting in the accumulation of toxic metabolites that can weaken the immune response. Solid tumor cells compete with CAR-T cells for glucose, lipids, and amino acids, leading to immune depletion and reduced treatment success rates.
Understanding how metabolism affects immune function is important for improving cancer treatment. Further research is needed to develop strategies to enhance immune cell survival and efficacy in metabolically hostile tumors.
Nutrient competition and tumor metabolic barriers
CAR-T cell therapy involves engineering T cells so that they can target and kill cancer cells. However, in solid tumors, these cells survive a competitive immunosuppressive environment. Tumor cells consume large amounts of glucose through glycolysis, reducing glucose available to CAR-T cells and impairing their activation, proliferation, and cytotoxicity.
In turn, toxic byproducts such as lactate and reactive oxygen species (ROS) are produced, further weakening immunity.
Further stress due to amino acid depletion and disruption of lipid metabolism may further reduce CAR-T cell function, persistence, and survival.
Glucose reprogramming to enhance CAR-T function
Glucose is the main fuel for activated effector T cells. Enhancing glucose uptake and utilization is an important strategy to improve CAR-T cell performance. Metabolic priming controls the nutrients that T cells receive during development, producing “memory-like” cells that persist longer in the body and are more dependent on mitochondrial metabolism and fatty acid oxidation.
Another important element in this process is genetic modification. Increasing the expression of glucose transporters, such as glucose transporter type 1 (GLUT1), allows CAR-T cells to take up more glucose, improving energy production and reducing fatigue.
Advanced strategies use alternative transporters such as glucose transporter type 3 (GLUT3). This works better under low glucose conditions, allowing CAR-T cells to survive even within nutrient-poor tumors.
Drugs can further support this process by targeting metabolic enzymes, improving mitochondrial function, promoting energy production, and reducing cellular stress. Examples discussed in this review include DCA, low-dose 2DG, enasidenib, PKM2 activation, and LDHA inhibition. Combining these methods could potentially maintain CAR-T cell activity even at low nutritional levels.
Lipid metabolism and CAR-T persistence
Although glucose supports immediate activity, lipid metabolism is essential for long-term survival and memory formation. CAR-T cells that rely on fatty acid oxidation (FAO) exhibit better persistence and durability.
Selecting specific co-stimulatory domains during CAR design promotes lipid-based metabolism and extends cell lifespan. For example, 4-1BB-based CAR designs tend to support fatty acid oxidation and memory-like persistence, whereas CD28-based designs more strongly support glycolytic effector activity.
Techniques such as FLASH (very high dose rate) radiotherapy can alter the tumor microenvironment, reducing immunosuppressive signals or increasing CAR-T cell infiltration into the tumor. In preclinical medulloblastoma models, FLASH radiotherapy is thought to reprogram macrophage lipid metabolism, create a less suppressive environment, and improve GD2 CAR-T cell infiltration and activation.
Furthermore, combining CAR-T therapy with drugs that induce ferroptosis (a type of cell death caused by lipid metabolism) provides a strategy to attack tumors. The cumulative effect of these advances may improve the overall survival and efficacy of CAR-T cells when used against solid tumors.
Amino acid deficiency and toxic metabolite strategies
Amino acids are essential for protein synthesis and immune signaling. Tumor cells consume important amino acids such as tryptophan and arginine, leaving CAR-T cells depleted, leading to decreased proliferation and increased fatigue.
Researchers developed CAR-T cells that express amino acid transporters, allowing them to compete for these nutrients more effectively. Additionally, new technologies for CAR-T cells may equip them with enzymes that help regenerate certain amino acids, such as arginine, making them less dependent on external sources.
Another major problem with CAR-T therapy is the accumulation of immunosuppressive substances such as kynurenine, which reduce T cell function and help maintain immune tolerance. One pharmacological approach is to inhibit IDO1, an enzyme that causes tryptophan depletion and kynurenine accumulation.
The researchers also engineered CAR-T cells to express enzymes that degrade or remove toxic metabolites produced in the tumor area, thereby allowing the engineered CAR-T cells to neutralize T-cell suppression in that area.
Personalized multipathway CAR-T metabolic design
The metabolic profile of tumors varies widely depending on the patient and cancer type. Future CAR-T therapies may be designed by combining multiple strategies targeting glucose, lipids, and amino acids to create personalized metabolic modifications tailored to each patient’s tumor environment.
In addition to using a combination of different methods to target different pathways, researchers are also developing dynamic and controlled systems to activate metabolic enhancement exclusively within the tumor environment, minimizing the potential for side effects. This is important because continued overexpression of some metabolic genes may pose long-term safety concerns.
This evolution is moving from the use of single-targeted therapies to the use of integrated and adaptable therapies. Increasing the metabolic flexibility of CAR-T cells may make them more resistant to the harsh environment of solid tumors and provide more durable therapeutic outcomes.
The future of metabolically enhanced CAR-T cells
Metabolic reprogramming has emerged as an important strategy to enhance the efficacy of CAR-T cell therapy in solid tumors. By optimizing the use of both lipids and glucose and addressing amino acid deficiencies in the tumor microenvironment, these approaches may help generate more durable and effective CAR-T cell therapies, but further clinical validation is required.
A combination of genetic modification, pharmacological intervention, and manufacturing advances will make it possible to develop CAR-T cells with improved persistence, functionality, and tumor-killing ability.
Importantly, integrating multiple pathways and individualized strategies has the potential to further improve clinical outcomes. However, many of these approaches are still in the experimental stage and are primarily tested in the laboratory or animal models.
Further research is needed to determine which strategies can safely enhance immune cell survival and efficacy in metabolically hostile tumors.
These advances highlight the potential for metabolically enhanced CAR-T cells to help advance cancer therapy and extend their success beyond hematologic malignancies to more challenging solid tumors.
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Reference magazines:
- Zheng, Z., Chen, Z., Zhang, Z., and Zheng, Z. (2026). Metabolic reprogramming of CAR-T cells: a multipronged strategy to overcome the immunosuppressive tumor microenvironment. Cell communication and signal transduction. Doi: 10.1186/s12964-026-02864-6 https://link.springer.com/article/10.1186/s12964-026-02864-6
