In the relentless battle against cancer, a pivotal metabolic player has emerged commanding intense scientific focus: glutamine. Once regarded simply as a common amino acid, glutamine’s critical involvement in tumor cell metabolism has redefined it as a “conditionally essential” nutrient within the cancer microenvironment. Despite its ubiquity in the human body, the extraordinary proliferative demands of cancer cells often outstrip both endogenous synthesis and external supply, precipitating localized glutamine depletion within tumors. This metabolic scarcity underscores a paradox—tumors rapidly consume glutamine for growth while simultaneously creating nutrient-starved niches, intensifying spatial metabolic heterogeneity that influences tumor progression and response to therapy.
Glutamine’s role in cancer transcends simple nutrient provision. It acts as a dual source of nitrogen and carbon essential for biosynthetic pathways indispensable for tumor expansion. The concept of “glutamine addiction” has crystallized in recent years, revealing how many tumors become dependent on glutamine to fuel the tricarboxylic acid (TCA) cycle and maintain bioenergetic and anabolic homeostasis. This heightened glutamine catabolism complements glycolysis-driven metabolism, a metabolic reprogramming hallmark initially characterized by the Warburg effect. Yet unlike the classic interpretation that tumors rely solely on glycolysis despite oxygen abundance, glutamine metabolism provides a critical anaplerotic input, sustaining the mitochondrial TCA cycle amid dynamic microenvironmental stresses.
At the biochemical core, glutamine is synthesized intracellularly by glutamine synthetase and imported across cell membranes primarily via specialized transporters such as ASCT2/SLC1A5 and LAT1, illustrating the multifaceted control over glutamine availability in cancer cells. Within mitochondria, glutaminase enzymatically deaminates glutamine to glutamate, which subsequently feeds into two principal metabolic fates. First, glutamate is converted into α-ketoglutarate by glutamate dehydrogenase or aminotransferases, replenishing TCA cycle intermediates vital for energy production and biosynthesis. Second, glutamate contributes to glutathione synthesis, a critical antioxidant that enhances cellular defenses against oxidative stress, further enabling tumor survival under hostile conditions.
The pivotal role of glutamine extends into nucleotide biosynthesis, where its nitrogen atoms are incorporated into purines and pyrimidines, the foundational molecules for DNA and RNA synthesis. This biochemical pathway supports the rapid cell cycle progression characteristic of malignant cells, underscoring glutamine’s integral influence in sustaining incessant cellular proliferation. Paradoxically, while tumors exhibit enhanced glycolysis with elevated lactate production, often diverting glucose carbons away from the mitochondria, mitochondria nonetheless remain functionally intact in many cancers. Glutamine-derived α-ketoglutarate thus replenishes the TCA cycle intermediates, sustaining mitochondrial metabolism despite alterations in glucose utilization.
Environmental conditions heavily sculpt glutamine metabolism. Under normoxic conditions, α-ketoglutarate enters the conventional oxidative TCA cycle, whereas hypoxic or mitochondrially impaired settings favor reductive carboxylation of α-ketoglutarate to citrate. This citrate then exits mitochondria to serve as a substrate for ATP citrate lyase, generating acetyl-CoA for fatty acid synthesis. Thus, glutamine metabolism intersects with lipid biosynthesis pathways essential for membrane formation and cell growth, illustrating the versatile metabolic roles glutamine occupies in tumor bioenergetics and macromolecular synthesis.
Pharmacologically targeting glutamine metabolism disrupts this metabolic network, attenuating lactate generation from glycolysis and undermining tumor energy balance. Beyond energy metabolism, glutamine’s influence pervades the tumor immune microenvironment. Immune cells also rely on glutamine to support activation, proliferation, and effector functions, especially in the nutrient-restrained tumor milieu. This creates a competitive battleground where tumor and immune cells vie for glutamine, affecting the efficacy of antitumor immune responses and immunotherapies.
Activated T effector cells ramp up both glycolysis and glutamine metabolism, increasing expression of transporters like SLC1A5 and SLC38A1, critical for glutamine uptake. Alterations in glutaminase activity shift T cell differentiation dynamics—genetic deletion of GLS1 promotes differentiation toward Th1 and CD8+ phenotypes while restraining Th17 cells. This shift occurs through modulation of transcriptional regulators such as T-bet and intracellular signaling pathways including mTORC1, highlighting glutamine metabolism’s immunomodulatory capacities. Conversely, glutamine deprivation facilitates regulatory T cell induction via AMPK-mTORC1 axis, suppressing cytotoxic immune activity and promoting immunosuppression.
These intricate metabolic dynamics underscore a metabolic tug-of-war within tumors, where glutamine scarcity impairs antitumor immunity while fueling malignant survival. Novel therapeutic approaches seek to leverage this metabolic vulnerability, either by restricting glutamine availability specifically in tumors or by restoring glutamine to enhance immune cell function. For instance, current studies show that tumor and dendritic cells compete for glutamine through the transporter SLC38A2, and exogenous glutamine supplementation can rescue dendritic cell function and bolster CD8+ T cell-mediated antitumor responses. Such strategies hold promise in overcoming resistance to immunotherapies, repositioning glutamine metabolism as an immunological and oncological target.
Moreover, glutamine metabolism interlinks intimately with immune checkpoint regulation. Glutamine deprivation induces expression of the immune inhibitory molecule PD-L1 in various cancers, facilitating immune escape. Molecularly, glutamine starvation activates signaling cascades involving EGFR/MEK/ERK/c-Jun pathways, upregulating PD-L1 and dampening immune surveillance. In bladder cancer and lung tumors, these alterations correspond with glutathione depletion and oxidative stress, further connecting glutamine metabolism to immune evasion mechanisms. Importantly, restoration of glutamine normalizes PD-L1 levels, and blockade of PD-1/PD-L1 interactions mitigates this escape, suggesting combinatory therapeutic avenues.
Additionally, glutamine influences B cell differentiation and antibody production. Inhibition of glutamine transport or glutaminase activity not only stifles tumor growth but also impairs humoral immune responses, highlighting the amino acid’s systemic immunometabolic role. This complexity expands the consideration of glutamine targeting from a narrow tumor metabolic disruption strategy toward broader immunomodulatory therapy with potential to reshape anti-cancer immunity and treatment outcomes.
In conclusion, glutamine occupies a central web of metabolic and immunological pathways that together orchestrate cancer progression, immune escape, and therapeutic resistance. Understanding the multifaceted biochemical pathways and signaling networks involving glutamine unveils novel insights into tumor biology and paves the way for innovative precision therapies. By straddling the domains of bioenergetics, biosynthesis, and immune modulation, glutamine metabolism represents a compelling therapeutic axis—offering hope for disrupting cancer’s adaptive resilience and enhancing immunotherapeutic efficacy in oncology’s next frontier.
Subject of Research:
Glutamine metabolism and its central role in tumor cell bioenergetics, biosynthesis, immune modulation, and therapeutic targeting.
Article Title:
The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting.
Article References:
Yan, X., Liu, C. The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting. Cell Death Discov. 11, 390 (2025). https://doi.org/10.1038/s41420-025-02683-7
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