Nutrient-gene therapy as a strategy to enhance CAR T cell function and overcome barriers in the tumor microenvironment

Abstract

Cancer immunotherapy is transforming the treatment landscape of both hematological and solid cancers. Although T-cell-based adoptive cell transfer (ACT) therapies have demonstrated initial success, several recurrent obstacles limit their long-term anti-tumor efficacy, including: (1) lack of antigen specificity; (2) poor long-term survival of transplanted T cells in vivo; and (3) a hostile tumor microenvironment (TME). While numerous approaches have been explored to enhance the antigen specificity of Chimeric Antigen Receptor (CAR) T-cell therapies, the field still lacks an effective strategy to optimize the long-term retention and in vivo expansion of engrafted T cells within the TME-a critical factor for the durable efficacy of T-cell-based immunotherapies for both blood and solid cancers. Here, we hypothesize that the success of CAR T-cell therapy can be enhanced by targeting donor T cells' ability to compete with cancer cells for key nutrients, thereby overcoming T-cell exhaustion and sustaining durable anti-tumor function in the TME. To explore this hypothesis, we first provide a comprehensively review of the current understanding of the metabolic interactions (e.g., glucose metabolism) between T cells and tumor cells. To address the challenges, we propose an innovative strategy: utilizing nutrient gene therapy (genetic overexpression of glucose transporter 1, GLUT1) to fortify the metabolic competency of adoptive CAR T-cells, deprive tumors of critical metabolites and ATP, and disrupt the TME. Altogether, our proposed approach combining precision medicine (adoptive CAR T-cell therapy) with tumor metabolism-targeting strategies offers a promising and cost-effective solution to enhance the efficacy and durability of ACT therapies, ultimately improving outcomes for cancer patients.

Keywords: Adoptive cell therapy; CAR T; Cancer immunotherapy; GLUT1; Gene therapy; Glucose; Metabolite; Nutrient; TME; Warburg effect.

Fig. 1

Comprehensive review of cancer immunotherapy (C.I.) studies over the last 80 years. This study highlights the potential metabolic barriers to the success of adoptive cell transfer (ACT) therapies by detailing the metabolic interactions between T cells and tumor cells within the tumor microenvironment (TME). To retrospectively examine the development of the cancer immunotherapy field, we utilized PubMed database to search all relevant studies, yielding 193,236 results between 1945 to January 18, 2025. To further narrow the scope, searches for “tumor microenvironment, cancer immunotherapy” and “metabolite, cancer immunotherapy” returned 28,576 and 1175 results, respectively. Additional searches for “TME, metabolite, cancer immunotherapy” and “GLUT1, cancer immunotherapy” yielded 415 and 63 results, respectively. These findings highlight the substantial interest in targeting TME within the cancer research field. There is significant variability in the number of studies focused on different immunotherapy techniques: CAR T-cell therapy (23,722 studies), TCR-T cell therapy (507 studies), tumor-infiltrating lymphocytes (TILs; 1604 studies), invariant natural killer T (2725 studies) and natural killer cells (10,644 studies). These numbers highlight the broad interest in CAR T-cell applications. Notably, a search for “CAR-T, metabolism-targeting” or “CAR-T, metabolite-targeting” yielded no results. However, searches for “CAR-T, GLUT1 overexpression”, “GLUT3 overexpression” and “GLUT1, nutrient, TFAM (mitochondrial transcription factor A), CAR-T”, returned five studies [–32, 35], four study [, –35], and one study [29], respectively. This limited number of studies underscores the novelty of our nutrient-competency-based strategy, which aims to improve the efficacy of CAR T-cells by addressing metabolic barriers within the TME

Fig. 2

A schematic diagram (Approach 1 for blood cancers) illustrating the strategy of developing a nutrient-competency and metabolism-enhanced CAR T-cell therapy for AML. A In current CAR T-cell therapies, adoptively transferred T cells may fail to compete with leukemia blasts for glucose uptake. Blasts are known to suppress T cells through inhibitory signals (e.g., PD-L1) and by depriving glucose from T cells, leading to T-cell exhaustion. Simultaneously, blasts exploit the Warburg effect (increased glycolysis) to fuel their uncontrolled proliferation and drive AML relapse. As a result, various cellular populations are present during AML relapse, including normal T cells, exhausted T cells and relapsed blasts. B To improve CAR T-cell therapy for AML, T cells can be genetically engineered to overexpress the GLUT1 transgene. GLUT1 overexpression enhances CAR T cells’ metabolic fitness and competitive glucose-uptake capabilities. By depriving blasts of glucose, the Warburg effect is reduced, potentially resulting in increased blast cell death (dual cytotoxicity) and improved therapeutic outcomes

Fig. 3

A schematic diagram illustrating the strategy of starving blasts to overcome the challenge of genetic heterogeneity in pre-designed CAR T-cell therapy for AML. A CAR T-cells bind to matched specific antigen 1 and induce targeted cytotoxicity in leukemia blasts. B Due to genetic heterogeneity, CAR T-cells engineered for specific antigen 1 fail to mount a cytotoxic response against leukemia blasts expressing antigen variant 2, leading to disease relapse and T-cell exhaustion. C CAR T-cell with GLUT1 overexpression deprive blasts of glucose, disrupt the Warburg effect, and inhibit uncontrolled blast proliferation. This approach provides an alternative strategy to circumvent the challenge of genetic heterogeneity in pre-designed CAR T-cell therapies. D In heterogeneous AML, engineered CAR T-cells with GLUT1 overexpression are drawn to a leukemia population composed of both blasts with a specific antigen 1 and blasts with antigen variants 2 or 3. These CAR T-cells exert dual cytotoxic effects: directly targeting antigen-specific leukemia blasts while simultaneously depriving both specific blasts and nearby non-specific blasts of glucose, thereby inhibiting uncontrolled blast proliferation

Fig. 4

A schematic diagram (Approach 2 for solid tumors) illustrating the action of metabolically starving tumor cells and their TME stromal components to disrupt the matrix barrier surrounding tumors. This disruption enhances the penetration of CAR T-cell therapies, enabling them to target and eliminate cancer stem cells more effectively, thereby improving outcomes in the fight against cancers

Fig. 5

A graphical summary of the tables and key findings from this review