In the relentless pursuit of innovative cancer therapies, a novel target is capturing the attention of the oncology research community: glutamine metabolism within the tumor microenvironment (TME). The amino acid glutamine, long recognized for its role in cellular metabolism, has emerged as a linchpin in the survival and proliferation of cancer cells. Recent scientific advances have illuminated the intricate mechanisms by which glutamine supports tumor growth, offering a new avenue for targeted metabolic intervention. This breakthrough promises to reshape therapeutic strategies and improve outcomes for patients battling various forms of cancer.
Glutamine functions as a critical nutrient that fuels tumor cells by providing both carbon and nitrogen essential for anabolic processes, energy production, and maintaining redox balance. Tumor cells exhibit an increased reliance on glutamine compared to normal cells, a phenomenon termed “glutamine addiction.” This metabolic reprogramming allows cancer cells to thrive in the nutrient-scarce and immunosuppressive tumor microenvironment. Understanding the molecular underpinnings of glutamine uptake and catabolism holds the key to effectively disrupting these metabolic dependencies and curbing tumor growth.
Central to glutamine’s role in cancer metabolism are specialized glutamine transporters embedded in the cellular membrane, which facilitate its uptake into tumor cells. Among these, the solute carrier family, including transporters such as SLC1A5, SLC7A5, and SLC38A2, has been shown to be upregulated in diverse malignancies. Therapeutic agents that inhibit these transporters aim to starve tumor cells by blocking glutamine influx, thereby depriving them of this vital resource. Such inhibitors represent a frontline strategy in metabolic cancer therapy due to their potential to selectively target tumor cells while sparing normal tissues.
One of the pioneering compounds in this class is V9302, a competitive antagonist that selectively binds to the glutamine transporter SLC1A5. Preclinical models in breast cancer have demonstrated that V9302 hampers glutamine transport, thereby promoting oxidative stress within tumor cells and triggering autophagy. These effects sensitize tumors to conventional chemotherapy and immune checkpoint inhibitors like anti-PD-1 antibodies, highlighting the promise of combination regimens. Innovative delivery systems incorporating V9302, such as reactive oxygen species (ROS)-responsive nanoparticles, have further enhanced targeted drug release and anti-tumor efficacy in preclinical uveal melanoma models.
Targeting another seminal transporter, SLC7A5, has also shown clinical promise. The inhibitor JPH203 binds with high affinity to SLC7A5, disrupting glutamine availability in tumor cells. Notably, JPH203’s efficacy has been validated in triple-negative breast cancer models where it not only alone curbs tumor progression but also acts synergistically with anti-PD-1 immunotherapy. This combinatorial effect potentiates immune activation and tumor regression, suggesting that metabolic blockade coupled with immune modulation could represent a transformative approach in resistant cancers.
Beyond the blockade of glutamine transport, a surge of interest centers on inhibiting glutaminase, the pivotal enzyme that converts glutamine to glutamate, facilitating glutamine catabolism and fueling the tricarboxylic acid (TCA) cycle. Targeting this enzymatic step directly disrupts cancer cell bioenergetics and biosynthesis. CB-839, a highly selective glutaminase inhibitor, has emerged as a frontrunner in this arena, demonstrating potent anti-proliferative effects in glutamine-dependent malignancies such as esophageal squamous cell carcinoma and lung cancer. By reducing glutaminase activity, CB-839 effectively limits the energy supply and biosynthetic precursors essential for tumor survival.
Advancements in nanotechnology have enabled the co-delivery of glutaminase inhibitors like CB-839 alongside photosensitizers to enhance photodynamic therapy (PDT) outcomes in gastric cancer. This multifunctional therapeutic strategy leverages the synergistic potential of metabolic inhibition and photoactivated cytotoxicity, resulting in greater tumor suppression. Moreover, novel glutaminase inhibitors such as IPN60090, when combined with CB-839, show promise in treating hematologic malignancies including myelodysplastic syndromes and acute myeloid leukemia by impairing NADPH-dependent cellular processes crucial for cancer cell proliferation.
Another remarkable compound in glutamine-targeted therapy is 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that irreversibly inhibits multiple enzymes involved in glutamine metabolism via covalent binding. Its efficacy in pancreatic ductal adenocarcinoma (PDAC) mouse models is particularly notable, where DON and its prodrug DRP-104 effectively suppress tumor proliferation and metastasis. The prodrug JHU-083, based on DON, offers an improved therapeutic index by selectively reducing tumor burden in lung cancer models without eliciting significant systemic toxicity, addressing a critical concern in metabolic cancer therapies.
The oncogene c-Myc, frequently dysregulated in cancer, upregulates glutaminase GLS1 expression and amplifies glutamine metabolism. The development of MYCi975, a novel MYC inhibitor, reveals a strategic front to disrupt this pathway. Treatment with MYCi975 in head and neck squamous cell carcinoma models significantly diminishes tumor cell proliferation and glutamine consumption. Moreover, dual inhibition combining MYCi975 and CB-839 synergizes to more effectively suppress tumor growth and metastasis than either agent alone, opening avenues for precision metabolic oncology.
KRAS-mutant tumors, notorious for their aggressive behavior, show upregulated expression of glutamine transporters and enzymes like GOT1 and GOT2 involved in the TCA cycle. Inhibiting transporters such as SLC7A5, SLC38A2, and mitochondrial glutamate carrier SLC25A22 presents strategic targets to thwart glutamine uptake and metabolism in these refractory cancers. Targeting this metabolic vulnerability holds immense therapeutic potential, especially in notoriously treatment-resistant KRAS-driven malignancies.
Beyond direct metabolic inhibition, metabolic-immunomodulatory strategies like the PD-L1-targeted metabolism and immunomodulator (PMIR) represent an innovative synthesis of immunotherapy and metabolism. PMIR curtails glutamine metabolism in tumors, thereby elevating glutamine availability within the TME, which enhances immune cell function. Simultaneously, PMIR suppresses PD-L1 expression on tumor cells, reversing immune evasion. This dual approach triggers immunogenic cell death, remodels the immunosuppressive TME, and robustly inhibits tumor progression and metastasis, underscoring the potential to combine metabolic reprogramming with immunotherapeutic interventions.
The clinical development of glutamine metabolism-targeted agents showcases significant progress toward realizing the therapeutic potential of metabolic vulnerabilities in cancer. These inhibitors of glutamine transport and catabolism have demonstrated encouraging efficacy and manageable safety profiles in diverse preclinical and early clinical settings. Nevertheless, the complexity of tumor metabolic networks and heterogeneity of glutamine dependency necessitate continued research to optimize treatment regimens, overcome resistance mechanisms, and identify patient populations most likely to benefit.
Intriguingly, combination therapies integrating glutamine inhibitors with other modalities such as chemotherapy, immunotherapy, and photodynamic therapy have exhibited enhanced antitumor responses. These multidimensional approaches leverage synthetic lethality and immune activation, indicating that targeting glutamine metabolism could serve as a critical axis in precision oncology. Personalized metabolic interventions, guided by biomarkers of glutamine dependence and metabolic flux analysis, represent the future frontier in cancer treatment.
Despite the remarkable advances, challenges persist in translating glutamine-targeted therapies from bench to bedside. Tumor metabolic plasticity, compensatory pathways, and potential off-target effects require sophisticated therapeutic designs and comprehensive mechanistic studies. The integration of systems biology, metabolomics, and advanced drug delivery systems will be crucial in tailoring glutamine metabolism inhibitors to clinical scenarios, maximizing efficacy while minimizing toxicity.
The burgeoning field of glutamine metabolism in the tumor microenvironment is rapidly redefining the landscape of cancer therapy. Harnessing glutamine’s central role offers a promising strategy to selectively impair tumor growth, overcome immune resistance, and enhance the benefits of existing treatment modalities. As research progresses, the intricate metabolic dance between cancer cells and their microenvironment reveals vulnerabilities ripe for exploitation, heralding a new era of cunning metabolic therapies poised to transform cancer care.
Subject of Research:
Glutamine metabolism as a therapeutic target in the tumor microenvironment for cancer treatment.
Article Title:
Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.
Article References:
Lv, H., Han, X., Yang, Y. et al. Glutamine: a new strategy for targeted metabolic therapy in the tumor microenvironment.
Cell Death Discov. 11, 459 (2025). https://doi.org/10.1038/s41420-025-02767-4
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02767-4
