A Glutamine Antagonist Prodrug Reprograms Dendritic Cells to Enhance Colorectal Cancer Immunotherapy

ABSTRACT: The tumor microenvironment (TME) imposes profound metabolic and immunosuppressive barriers that compromise the functionality of immune cells and limit effective anti-tumor responses. A hallmark of many tumors is their heightened dependency on glutamine as a metabolic substrate, which leads to glutamine depletion within the TME. This glutamine scarcity impairs the function of dendritic cells (DCs), resulting in defective antigen presentation and diminished activation of CD8⁺ cytotoxic T cells. Here, we report T26, a bifunctional immunometabolic prodrug composed of JHU083 (a glutamine antagonist) and MSA-2 (a STING agonist), designed to restore DC functionality and enhance anti-tumor immunity. T26 effectively suppresses tumor growth in colorectal cancer (CRC) models by reprogramming the TME toward a more immunostimulatory state. Mechanistically, T26 promotes DC maturation, enhances antigen presentation, and facilitates robust CD8⁺ T cell responses, leading to durable tumor suppression. Importantly, DC depletion experiments demonstrate that the anti-tumor efficacy of T26 is critically dependent on DC activation. Moreover, T26 reprograms tumor-derived extracellular vesicles (EVs), enhancing their capacity to transmit immunostimulatory signals and support CD8⁺ T cell–mediated cytotoxicity. In addition, T26 exhibits strong synergistic effects when combined with standard chemotherapy, immune checkpoint blockade, and anti-angiogenic therapy, further potentiating therapeutic efficacy. Collectively, these findings position T26 as a promising candidate for combination cancer immunotherapy, offering a dual-acting strategy that overcomes metabolic suppression and immune evasion in the TME to improve treatment outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE296658 | GEO | 2026/03/06

REPOSITORIES: GEO