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

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.