FOR IMMEDIATE RELEASE
Orthomolecular Medicine News Service, November 14, 2025

Why Targeting Glutaminolysis Fails: The Cost of Disrupting Essential Physiology

by Richard Z. Cheng, M.D., Ph.D.
Editor-in-Chief, Orthomolecular Medicine News Service

Abstract

The glutamine-to-glutamate metabolic pathway (glutaminolysis) has been widely heralded in oncology as a "fuel pocket" target for proliferating cancer cells. Yet despite decades of preclinical enthusiasm and early clinical trials, meaningful therapeutic advances remain elusive. This article argues that the fundamental flaw lies in the premise: glutamine is a conditionally essential nutrient for normal host physiology (immune, gut, mitochondrial, redox) and systemic blockade therefore threatens the terrain as much as the tumour. From an orthomolecular perspective, restoring metabolic balance - rather than depriving essential nutrients - provides a more rational, sustainable strategy for integrative oncology care.

The following discussion was inspired by a question raised during my presentation at the 25th Annual Cancer Care Reimagined Conference at the Riordan Clinic (November 2025). The audience asked whether targeting glutaminolysis could be a viable metabolic approach to cancer therapy. This article expands on my answer - explaining why, from both biochemical and orthomolecular perspectives, this strategy represents a conceptual dead end in cancer R&D.

This case exemplifies the larger error of attacking essential metabolism instead of restoring it - a recurring theme across modern chronic disease research.

1. The Rise of Glutaminolysis as a Cancer Target

Since the early 2010s, cancer metabolism research has emphasized the role of glutamine in tumor cell survival, proliferation, and biosynthesis. Studies documented that many cancer cells up-regulate glutamine transporters (e.g., SLC1A5/ASCT2), glutaminase (GLS1/GLS2) and downstream anaplerotic pathways feeding the TCA cycle [1-3].

In the influential review "Glutaminolysis: A Hallmark of Cancer Metabolism," Yang et al. (2017) described glutamine as "the most abundant circulating amino acid ... critical for many fundamental cell functions in cancer cells" including mitochondrial metabolism, antioxidant generation, and biosynthesis [1].

From these findings arose the prevailing logic: inhibit glutamine metabolism → deprive cancer cells of fuel, biosynthetic precursors, redox protection → kill or slow tumor growth.

2. Glutamine's Pivotal Role in Normal Host Physiology

What is often under-emphasized in tumor-centric research is that glutamine is not "junk fuel" in the body - it serves essential roles in normal physiology. In states of stress (infection, trauma, cancer), glutamine becomes conditionally essential. It supports enterocytes, lymphocytes, glutathione synthesis, acid-base balance, and mitochondrial substrate pools [2, 3].

For example:

• Enterocytes and gut-mucosa require glutamine for integrity; glutamine deprivation can lead to gut barrier breakdown [3].
• Immune cells (especially lymphocytes) are high glutamine consumers; depriving them may impair host-defense.
• Redox regulation: glutamine supplies glutamate for glutathione synthesis, a key antioxidant.
• In skeletal muscle, glutamine serves as a nitrogen shuttle and reservoir, modulating acid-base homeostasis during stress and injury.

Thus, glutamine depletion is a systemic insult - not a targeted therapy - and contradicts the principle of preserving host integrity.

3. Why the Therapeutic Strategy Has Fallen Short

Despite the compelling biochemical rationale, clinical translation has been disappointing.

Key reasons:

• Metabolic plasticity: tumor cells can compensate by increasing reliance on glucose or amino acid fermentation when glutamine is restricted. However, as emphasized in the mitochondrial metabolic theory of cancer, most tumor cells appear unable to efficiently oxidize fatty acids or ketones for fuel due to mitochondrial defects [3-5]. This apparent paradox between metabolic flexibility and mitochondrial impairment reflects differences across tumor types and stages - a complexity that underscores the need for individualized, terrain-based metabolic care.
• Tumor heterogeneity: not all tumors are truly glutamine-addicted; biomarkers to identify such subtypes remain weak [3, 4].
• Host toxicity: because glutamine is vital for normal tissues, inhibition provokes side-effects that limit dosing [2].
• Minimal survival benefit so far: While early phase trials (e.g., GLS inhibitor CB-839) showed modest signals, large scale impactful benefit remains absent (to date).

In their 2023 review "Targeting glutamine metabolism as a therapeutic strategy for cancer," Jin et al. noted "many hurdles ... before we develop a clinically effective drug." [4]

Indeed, telaglenastat failed to improve outcomes in randomized Phase II studies of renal cell carcinoma (CANTATA; NCT02071862) and triple-negative breast cancer (ENDEVOR; NCT03428217), leading to discontinuation of its development program [4].

From an orthomolecular vantage, the problem is that this approach remains deprivation-based rather than restoration-based, making it vulnerable to both host injury and tumor adaptation.

4. Beyond "Starving the Tumor": Why Restriction Alone Fails

Cancer metabolic therapy should not be focused solely on restricting tumor energy supply, because there is only so much one can achieve in that respect. Tumor cells possess extensive metabolic flexibility, while the host terrain - mitochondria, immune system, redox status - suffers under further deprivation.

Cancer is a multifactorial disease, influenced by toxins, nutritional deficits, inflammation, immune dysregulation, endocrine disruption, and psychosocial stress [6]. Therefore, Integrative Oncology requires a multi-angle approach, simultaneously addressing detoxification, micronutrient repletion, mitochondrial repair, immune modulation, and psychological resilience [7-9].

Many in the metabolic-oncology field remain narrowly fixated on "killing" cancer cells, often overlooking that terrain restoration is equally - and often more - important than tumor-cell killing. Decades of cytotoxic strategies have yielded minimal survival benefit. Without correcting the internal biochemical environment that permitted malignant adaptation, any attempt to "starve" the tumor remains transient and self-defeating.

5. Orthomolecular Perspective: Restoration, Not Restriction

Orthomolecular Medicine, as Linus Pauling proposed, seeks to optimize molecular conditions for health. From this standpoint, cancer therapy should aim to restore mitochondrial and redox homeostasis, not deprive essential nutrients.

Key strategies include:

• Micronutrient sufficiency: vitamins C, D3, E, B-complex, Mg, Zn, Se [10].
• Mitochondrial support: CoQ10, α-lipoic acid, N-acetylcysteine, carnitine.
• Metabolic modulation: low-carbohydrate/ketogenic nutrition, intermittent fasting, detoxification of heavy metals and endocrine disruptors.
• Systems restoration: immune balance, hormonal optimization, circadian alignment, and stress reduction.

This restoration-based model strengthens host resilience and complements targeted or conventional therapies - the foundation of Integrative Orthomolecular Cancer Therapy (IOCT) and the Triple-Principle Intervention Model (TPIM) discussed in my From Mutation to Metabolism trilogy [7].

6. Practical Implications for Integrative Cancer Care

• Assess the host terrain first: evaluate micronutrient status, mitochondrial function, immune competence, gut integrity, and toxin burden before any metabolic intervention.
• Use biomarkers judiciously: ^18F-fluoroglutamine (FGln) PET may help identify truly glutamine-dependent tumors [3].
• Prioritize restoration: ensure detox pathways and nutritional sufficiency are optimized so that therapeutic stress is tolerable.
• Favor restoration over restriction: metabolic therapies such as intermittent fasting, mild ketosis, and micronutrient support improve redox homeostasis without harming essential physiology.

7. Conclusion: From Suppression to Restoration

While targeting glutaminolysis once appeared mechanistically elegant, it is biochemically unsound and clinically futile. Tumors evolve; hosts deteriorate.

True progress in cancer care lies in shifting from metabolic suppression to metabolic restoration - from mechanism-focused to root-cause-driven, from a conventional single-focus to a multi-angle integrative approach - from the obsession with killing cells to rebuilding the biological terrain that sustains health.

As articulated in my From Mutation to Metabolism series (Parts I-III) [8], the next era of oncology must integrate orthomolecular principles, metabolic rehabilitation, and systems biology into both research and practice.

Starving the tumor must never mean starving the host.
Restoration, not restriction, is the future of metabolic cancer care.

About the Author

Richard Z. Cheng, M.D., Ph.D. - Editor-in-Chief, Orthomolecular Medicine News Service ( orthomolecular.org); Board Director, Riordan Clinic

Dr. Cheng is a U.S.-based, NIH-trained, board-certified physician specializing in integrative cancer therapy, orthomolecular medicine, functional & anti-aging medicine. He maintains active practices in both the United States and China.

A Fellow of the American Academy of Anti-Aging Medicine and a Hall of Fame inductee of the International Society for Orthomolecular Medicine, Dr. Cheng is a leading advocate for nutrition-based, root-cause health strategies. He also serves as an expert reviewer for the South Carolina Board of Medical Examiners, and co-founded both the China Low Carb Medicine Alliance and the Society of International Metabolic Oncology.

Dr. Cheng offers online Integrative Orthomolecular Medicine consultation services.
📰 Follow his latest insights on Substack: https://substack.com/@rzchengmd

References

1. Yang, L.; Venneti, S.; Nagrath, D. Glutaminolysis: A Hallmark of Cancer Metabolism. Annual Review of Biomedical Engineering 2017, 19, (Volume 19, 2017), 163-194. DOI: 10.1146/annurev-bioeng-071516-044546; Available online: https://www.annualreviews.org/content/journals/10.1146/annurev-bioeng-071516-044546.

2. Jin, L.; Alesi, G.N.; Kang, S. Glutaminolysis as a Target for Cancer Therapy. Oncogene 2016, 35, (28), 3619-3625. DOI: 10.1038/onc.2015.447.

3. Wang, Z.; Liu, F.; Fan, N.; Zhou, C.; Li, D.; Macvicar, T.; Dong, Q.; Bruns, C.J.; Zhao, Y. Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies. Front. Oncol. 2020, 10. DOI: 10.3389/fonc.2020.589508.; Available online: https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.589508/full.

4. Jin, J.; Byun, J.-K.; Choi, Y.-K.; Park, K.-G. Targeting Glutamine Metabolism as a Therapeutic Strategy for Cancer. Exp Mol Med 2023, 55, (4), 706-715. DOI: 10.1038/s12276-023-00971-9; Available online: https://www.nature.com/articles/s12276-023-00971-9.

5. Seyfried, T.N. Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer; Wiley, 2012.; Available online: https://www.wiley.com/en-us/Cancer+as+a+Metabolic+Disease%3A+On+the+Origin%2C+Management%2C+and+Prevention+of+Cancer-p-9780470584927.

6. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The next Generation. Cell 2011, 144, (5), 646-74. DOI: 10.1016/j.cell.2011.02.013; Available online: http://linkinghub.elsevier.com/retrieve/pii/S0092867411001279 http://www.ncbi.nlm.nih.gov/pubmed/21376230.

7. Cheng, R. From Mutation to Metabolism: Toxins, Mitochondria, and Integrative Orthomolecular Cancer Therapy (IOCT) - Implications for ASCVD and T2DM. 2025. DOI: 10.20944/preprints202510.1142.v1; Available online: https://www.preprints.org/manuscript/202510.1142.

8. Cheng, R.Z. From Mutation to Metabolism: Environmental and Dietary Toxins as Upstream Drivers of Mitochondrial Dysfunction and Chronic Disease. 2025. DOI: 10.20944/preprints202509.1767.v1; Available online: https://www.preprints.org/manuscript/202509.1767/v1.

9. Cheng, R.Z. From Mutation to Metabolism: Root Cause Analysis of Cancer's Initiating Drivers. 2025. DOI: 10.20944/preprints202509.0903.v1; Available online: https://www.preprints.org/manuscript/202509.0903/v1.

10. Levy, T.E. Hidden Epidemic: Silent Oral Infections Cause Most Heart Attacks and Breast Cancers: Levy, JD: 9780983772873: Amazon.Com: Books. Available online: https://www.amazon.com/Hidden-Epidemic-Infections-Attacks-Cancers/dp/0983772878/ref=sr_1_1?crid=27896O0DO4F8V&keywords=hidden+pandemic+by+levy&qid=1649867812&sprefix=hidden+pandemic+by+levy%2Caps%2C88&sr=8-1 (accessed 14 April 2022).

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