Cancer’s changing fuel systems: making sense of metabolic approaches
Explore how adaptable fuel systems shape resistance—and what research shows about metabolic targets, natural compounds and repurposed medicines.
Page 8 of the hub that unpacks the 2026 Cancer Stem Cells and Drug Resistance Review.
The review places metabolic flexibility at the centre of the CSC-resistance problem. It describes cancer stem-like cells not as cells with one fixed fuel preference, but as cells capable of changing how they make energy and protect themselves when they encounter treatment, low oxygen, immune pressure or nutrient stress.
Many cancer cells use high levels of glycolysis—rapid glucose breakdown, often with lactate production even when oxygen is present. This is the biology behind the Warburg effect. But the review cautions against treating that as the whole metabolic story. CSC-like cells may switch between glycolysis and oxidative phosphorylation (OXPHOS), use fatty acids and amino acids, and strengthen antioxidant systems that help them survive chemotherapy, radiation and hostile tumour conditions.
\text{glycolysis} \;\leftrightarrow\; \text{OXPHOS} \;\leftrightarrow\; \text{fatty-acid oxidation} \;\leftrightarrow\; \text{glutamine / amino-acid use}
The key point: Cancer metabolism is not one fuel tank. It is an adaptable energy network. A cancer cell may slow one pathway and increase another; a therapy that stresses glucose use may select for cells that rely more heavily on mitochondria, fats or amino acids. This is why “sugar feeds cancer, so remove sugar” is an incomplete interpretation of genuine cancer biology.[link.springer]
The research challenge is therefore not merely to deprive a tumour of a nutrient. It is to identify, for a particular cancer and treatment context, whether there is a metabolic dependency that cannot easily be bypassed—and whether it can be targeted safely in combination with standard therapy.
The metabolic pathways in the 2026 treatment resistance review
Pathway in the review | What it does for CSC-like cells | Strongest current evidence signal | Examples being investigated |
Glycolysis | Rapid energy and building blocks; often supports growth in low oxygen | Strong biological and imaging evidence; direct therapeutic targeting remains mostly early clinical/preclinical | 2-deoxy-D-glucose (2DG), lonidamine, lactate/MCT strategies; dietary carbohydrate restriction remains unproven as cancer treatment |
OXPHOS / mitochondria | Energy production, survival under stress, mitochondrial control of apoptosis and redox balance | One of the strongest CSC-metabolism research signals; real clinical trials, but no universal OXPHOS-targeting standard | Metformin, IACS-010759 and other complex-I strategies; devimistat/CPI-613; mitochondrial combinations |
Fatty-acid oxidation | Energy, NADPH/redox protection and membrane-building under stress | Strong preclinical signal in selected cancers; little established clinical translation specifically for CSCs | CPT1/FAO inhibitors such as etomoxir or teglicar; statin/mevalonate research; no validated dietary-fat protocol |
Glutamine metabolism | Feeds the TCA cycle, nucleotide synthesis, antioxidant glutathione and metabolic escape | Strong mechanistic and trial signal; mixed/ongoing clinical translation | Glutaminase inhibitors such as telaglenastat/CB-839 in selected trials |
Serine / one-carbon metabolism | Supports DNA building blocks, methylation and antioxidant capacity | Important and growing preclinical/translational signal | Enzyme-targeting and dietary-restriction concepts largely experimental |
Redox / ROS defences | Keeps reactive oxygen species low enough for CSC-like cells to survive DNA damage and therapy | Strong mechanistic signal; difficult therapeutic balance because normal cells also need redox protection | Glutathione/thioredoxin strategies, ferroptosis approaches, pro-oxidant combinations |
Autophagy | Cellular recycling during nutrient shortage, low oxygen and treatment stress | Extensive laboratory and early clinical work; results highly context-specific | Hydroxychloroquine/chloroquine combinations; not established as universal cancer care |
This table is not a list of treatments to take.
It is a map of the targets being studied because of the exact flexibility described in the review.
Strongest research signals
1. OXPHOS and mitochondrial dependence
Evidence signal: strong preclinical + active clinical-trial field
This is arguably the most developed metabolic theme arising from CSC research. Many—but not all—CSC-like populations show increased reliance on mitochondrial respiration, especially after treatment or during metastatic and nutrient-stress conditions. If rapidly dividing tumour cells are more dependent on glycolysis, a surviving slow-growing population may sometimes lean more heavily on mitochondria and OXPHOS.[link.springer]
This is why metformin appears repeatedly in CSC discussions. It can inhibit mitochondrial complex I, reduce mitochondrial energy production and activate AMPK-related stress signalling. Researchers have studied it in combinations with chemotherapy and targeted therapy, and in ovarian-cancer research a phase II study reported a reduction in ALDH-positive/CD133-positive stem-like cells alongside cisplatin treatment. That is an interesting human signal—not proof of a universal effect, but more than a cell-dish observation.
Other mitochondrial approaches discussed in the wider field include:
IACS-010759: an investigational complex-I inhibitor.
Devimistat / CPI-613: a mitochondrial metabolism-directed agent studied in leukaemias and selected solid tumours.
Phenformin: a more potent biguanide than metformin, but with a substantially less favourable safety profile, particularly lactic-acidosis risk.
Venetoclax-based AML combinations: not primarily marketed as metabolic therapy, but important because AML stem-like cells can show mitochondrial/OXPHOS dependence and venetoclax combinations can exploit metabolic vulnerabilities.
Reader takeaway: Metformin is a legitimate discussion point when a person has diabetes, insulin resistance, polycystic ovarian syndrome, or a cancer-specific trial opportunity. It is not automatically an anti-CSC medicine for every person with cancer. Kidney function, weight loss, appetite, dehydration risk and drug combinations matter.
2. Glutamine and amino-acid dependence
Evidence signal: strong mechanistic biology + cancer-specific clinical trials
Glutamine is not just “protein.” Cancer cells can use it to refill the TCA cycle, make nucleotides for DNA and RNA, produce lipids and maintain glutathione, an important antioxidant defence. This makes glutamine metabolism particularly relevant to cells trying to repair damage, survive oxidative stress and adapt when glucose or oxygen is limited.
The main drug-development strategy is to inhibit glutaminase, the enzyme that helps convert glutamine into glutamate. Telaglenastat (CB-839) has entered clinical trials across several cancers, including renal-cell cancer, melanoma, lung cancer, breast cancer and blood cancers. Results so far have not created a broadly approved “glutamine-targeting” cancer treatment, but this is a genuine clinical-research pathway—not merely an integrative theory.
Reader takeaway: Do not try to create a personal “glutamine-free” cancer diet. Glutamine is central to normal gut, immune and muscle biology, and dietary removal is not a validated way to deprive a tumour of glutamine. The clinical question is whether a specific cancer has a druggable glutamine-metabolism dependency.
3. Redox balance, ROS and ferroptosis
Evidence signal: strong CSC mechanism + early translational development
Many CSC-like cells maintain lower levels of reactive oxygen species, or ROS, than more differentiated cancer cells. This can help them avoid oxidative damage, survive radiation or chemotherapy and preserve mitochondrial function. The review identifies antioxidant systems—particularly glutathione-related networks—as a survival advantage and a possible vulnerability.
The research challenge is that ROS are not simply “bad” or “good.” Too little oxidative stress can protect a cancer cell; too much can damage cancer cells but also normal tissues. Researchers are therefore studying:
Glutathione depletion or thioredoxin-system inhibition.
Ferroptosis: a regulated, iron-dependent form of cell death driven by lipid peroxidation.
Carefully designed pro-oxidant combinations intended to overwhelm cancer-cell defences while preserving normal tissue as much as possible.
Reader takeaway: This is a reason to be cautious about blanket advice to take high-dose antioxidant supplements during chemotherapy or radiation. “Antioxidant” is not automatically protective in every treatment context, and “pro-oxidant” is not a safe self-treatment strategy.
4. Fatty-acid oxidation and lipid metabolism
Evidence signal: substantial preclinical signal; clinical translation is still early
Under stress, some CSC-like cells can use fatty acids as fuel through fatty-acid oxidation, often abbreviated FAO. This can provide ATP, NADPH for redox control and metabolic flexibility when glucose use is restricted. The review also describes lipid metabolism as part of a larger survival network rather than a single universal vulnerability.
Researchers are studying inhibitors of CPT1, an important gateway enzyme for fatty acids entering mitochondria. Examples include etomoxir and teglicar/ST1326. These are research tools or investigational approaches; they are not evidence that either a very low-fat or very high-fat diet will target CSCs.
This is especially relevant to ketogenic claims. Ketogenic diets reduce carbohydrate intake, but they also increase the availability of fats and ketones. Whether that helps, harms or makes no meaningful difference depends on the cancer model, metabolic context, nutritional state and treatment—there is no one-size-fits-all answer.
Reader takeaway: “Cancer uses fat” does not prove that low-fat eating treats cancer, just as “cancer uses glucose” does not prove that carbohydrate removal treats cancer.
5. Glycolysis and lactate
Evidence signal: foundational cancer biology; direct targeting remains difficult
Glycolysis remains an important target because many tumours take up glucose avidly and release lactate. Lactate is not merely waste: it can help shape acidity, immune suppression and signalling within the tumour microenvironment.[cell]
Agents such as 2-deoxy-D-glucose (2-DG) and lonidamine have been explored to interfere with glucose metabolism, but direct glycolysis inhibition can also affect normal tissues that need glucose. This contributes to the gap between powerful laboratory results and modest clinical translation.
Reader takeaway: The Warburg effect is real; the conclusion that dietary sugar deprivation is a proven cancer therapy is not.
Natural compounds: signals worth knowing
This is where integrative conversations often become most interesting—and most vulnerable to overstatement. Natural compounds can have multi-target effects, which is attractive in a networked system like CSC metabolism. But multi-target activity in a cell study also makes it hard to know which effect matters in a person, whether the necessary concentration reaches tumour tissue, and whether it helps or hinders conventional therapy.
Compound | Main metabolic / CSC-related research signal | Strongest evidence type | Honest current position |
Berberine | AMPK activation; complex-I and glucose-metabolism effects; ABC transporter and Wnt-related signals | Cell and animal models; limited human metabolic evidence | Interesting “metformin-like” research lead; not proven to treat cancer or CSCs |
Sulforaphane | Nrf2/redox signalling, epigenetic regulation, CSC markers and detoxification pathways | Strong preclinical work; early human biomarker studies | A leading dietary-compound research candidate; no proof it eliminates CSCs or controls progression |
Curcumin | NF-κB, PI3K/AKT/mTOR, mitochondrial and redox pathways; autophagy and apoptosis | Extensive preclinical literature; small, heterogeneous human studies | High-interest multi-pathway compound; bioavailability and interaction limits remain major issues |
EGCG / green-tea compounds | Mitochondrial, redox, growth-signalling and CSC-marker effects | Cell/animal work; observational and limited intervention data | Food-level tea is not the same as concentrated extract; extract-related liver and drug-interaction issues matter |
Quercetin | Glucose transport, PI3K/AKT, mitochondrial and drug-efflux pathways | Mostly cell/animal studies | Interesting in combination models; no proof of clinical CSC or resistance reversal |
Resveratrol/ pterostilbene | Mitochondrial stress, AMPK, redox and stemness-related pathways | Mainly preclinical | Research lead, not a cancer-metabolism treatment |
Melatonin | Mitochondrial/redox and circadian-metabolic signalling | Mixed clinical symptom-support literature; CSC claims largely preclinical | Potentially relevant for defined symptom or sleep discussions, not established metabolic cancer therapy |
The most honest conclusion is that sulforaphane, curcumin, berberine, quercetin and EGCG have the widest preclinical CSC/metabolism literature, but none has yet cleared the clinical-evidence threshold for being called a CSC-targeting treatment.
Reviews of natural compounds themselves flag poor bioavailability, rapid metabolism, product variation, tumour heterogeneity and lack of robust clinical validation as key obstacles.
Repurposed medicines: the more actionable conversations
Medicine or class | Metabolic target | Strongest evidence signal | Appropriate framing |
Metformin | Mitochondrial complex I, AMPK, insulin signalling | Diabetes standard care; multiple cancer trials; selected early CSC-related human signals | Discuss if there is diabetes, insulin resistance or a suitable cancer-specific trial |
Statins | Mevalonate/cholesterol pathway, membrane and prenylation biology | Strong cardiovascular evidence; cancer/CSC data mostly observational and preclinical | Useful where cardiovascular indication exists; not a general anti-CSC prescription |
Aspirin / NSAIDs | COX/PGE2, inflammation and tumour microenvironment signalling | Defined prevention roles in selected contexts; cancer-treatment evidence is setting-specific | Discuss only where a clinician can assess bleeding and treatment risks |
Hydroxychloroquine / chloroquine | Autophagy and lysosomal recycling | Many combination trials; inconsistent results | A genuine clinical-research strategy, not a self-directed cancer therapy |
Dichloroacetate (DCA) | Pyruvate dehydrogenase / glycolysis–mitochondria switching | Interesting laboratory and very early human research | Experimental; neuropathy, interaction and product-quality concerns |
Ferroptosis / redox agents | Lipid peroxidation, glutathione and GPX4-related defences | Strong preclinical rationale; early translational work | Not a supplement strategy; mostly a future clinical-trial direction |
The realistic integrative message
People should not be told, “There is nothing here.” because there is clearly lots happening here:
Metabolism is a serious field of cancer and CSC research.
Mitochondria, OXPHOS, glutamine, redox balance, autophagy, lipid metabolism and glycolysis are all legitimate targets.
Metformin, hydroxychloroquine, glutaminase inhibitors, mitochondrial agents, ferroptosis approaches and metabolic combinations are already part of the clinical-research landscape.
Several food-derived compounds have enough mechanistic and preclinical signal to justify careful scientific interest.
Re-testing, molecular profiling and clinical-trial review after progression can sometimes identify a more relevant therapeutic vulnerability.
But readers also need to hear the other half of the truth:
The same metabolic plasticity that makes these targets exciting can make simplistic protocols unreliable.
The evidence strength varies enormously between a compound changing a marker in a dish and a treatment improving survival in people.
Nutrition, muscle preservation, symptom control, blood-glucose management and completion of effective treatment are not secondary concerns; they are part of the biology that determines what a person can tolerate and benefit from.
The safest and most productive place for metabolic experimentation is usually a cancer-specific trial or a collaborative plan involving the oncologist, oncology pharmacist and oncology dietitian.
Further reading
Core Cancer Stem Cell Metabolism
Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets
https://doi.org/10.1186/s43556-026-00516-2
The anchor review.Metabolic Plasticity and Cancer Stem Cell Metabolism: Exploring the Glycolysis–OXPHOS Switch as a Mechanism for Resistance and Tumorigenesis
https://doi.org/10.1007/s12015-025-10956-y
Detailed current review of glycolysis–OXPHOS switching, glutamine, FAO, hypoxia and treatment resistance.The Metabolic Landscape of Cancer Stem Cells
https://pmc.ncbi.nlm.nih.gov/articles/PMC12109792/
Accessible 2025 review covering OXPHOS, lipids, glutamine, redox biology and selected clinical trials.Emerging Therapies in Cancer Metabolism
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00265-6
Broad overview of metabolic drug development and clinical-trial progress.[cell]Targeting Mitochondrial Metabolism for Precision Medicine in Cancer
https://doi.org/10.1038/s41418-022-01022-y
Strong reference for mitochondrial metabolism, glutaminase, FAO and redox-targeting drug-development strategies.
Metabolism: more flexible than “sugar feeds cancer”
The Metabolic Landscape of Cancer Stem Cells
International Journal of Molecular Sciences. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12109792/
an accessible broader overview of CSC metabolism, including mitochondrial dependence, lipid metabolism, glutamine, redox balance and emerging therapeutic approaches.Metabolic Plasticity and Cancer Stem Cell Metabolism: Exploring the Glycolysis–OXPHOS Switch as a Mechanism for Resistance and Tumorigenesis
Stem Cell Reviews and Reports. 2025.
https://doi.org/10.1007/s12015-025-10956-y
the idea that CSC-like cells may shift between glycolysis and OXPHOS in response to oxygen, nutrients and treatment pressure.
OXPHOS and mitochondria
Targeting Mitochondrial Metabolism for Precision Medicine in Cancer
Cell Death & Differentiation. 2022.
https://doi.org/10.1038/s41418-022-01022-y
mitochondrial metabolism, complex-I targeting, glutamine, fatty-acid oxidation, redox biology and the limits of translating metabolic mechanisms into treatment.[nature]Metabolic adaptations in cancer stem cells: A key to therapy resistance
Seminars in Cancer Biology. 2024.
https://www.sciencedirect.com/science/article/pii/S0925443924001534
CSC mitochondrial adaptation, OXPHOS dependency, treatment resistance and the rationale for OXPHOS-targeting drugs entering clinical trials.Emerging Therapies in Cancer Metabolism
Cell Metabolism. 2023.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00265-6
the broader clinical-development landscape for metabolic therapies, including mitochondria, glycolysis, nutrient use and trial-stage agents.
Glycolysis, glucose and lactate
Targeting Cancer Metabolism in the Era of Precision Oncology
Nature Reviews Drug Discovery. 2022.
https://doi.org/10.1038/s41573-021-00339-6why high glucose use in cancer is real biology, but direct metabolic targeting is difficult; also useful for explaining why only a limited number of metabolism-directed cancer medicines have reached clinical use.
Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets
https://doi.org/10.1186/s43556-026-00516-2
the review’s explanation that cancer stem-like cells may not be fixed glycolytic cells, and may shift between glycolysis and OXPHOS as conditions change.
Fatty-acid oxidation and lipid metabolism
The Metabolic Landscape of Cancer Stem Cells
https://pmc.ncbi.nlm.nih.gov/articles/PMC12109792/
fatty-acid oxidation as a possible source of ATP, NADPH and metabolic flexibility in selected CSC-like states; useful for your caution that this does not validate a high-fat or low-fat “CSC diet.”Targeting Mitochondrial Metabolism for Precision Medicine in Cancer
https://doi.org/10.1038/s41418-022-01022-y
fatty-acid oxidation, CPT1-related strategies and the early state of clinical translation.
Glutamine, serine and amino-acid pathways
The Metabolic Landscape of Cancer Stem Cells
https://pmc.ncbi.nlm.nih.gov/articles/PMC12109792/
glutamine as a substrate for TCA-cycle replenishment, biosynthesis and glutathione/redox defence; also useful for the caution against trying to create a personal “glutamine-free” diet.Targeting Mitochondrial Metabolism for Precision Medicine in Cancer
https://doi.org/10.1038/s41418-022-01022-y
glutaminase inhibitors, amino-acid metabolism and the clinical-development context for agents such as telaglenastat/CB-839.Emerging Therapies in Cancer Metabolism
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00265-6
the wider drug-development field around nutrient dependencies, including glutamine-targeting approaches.
Redox, ROS and ferroptosis
Targeting Cancer Stem Cell Redox Metabolism to Enhance Therapy Responses
Seminars in Cancer Biology. 2019.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6614864/
the premise that CSC-like cells can maintain lower ROS and stronger antioxidant systems, and the rationale for targeting glutathione, thioredoxin and redox vulnerabilities.Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets
https://doi.org/10.1186/s43556-026-00516-2
the review’s discussion of antioxidant defences, mitochondrial/redox adaptation and ferroptosis as an emerging strategy.Targeting Mitochondrial Metabolism for Precision Medicine in Cancer
https://doi.org/10.1038/s41418-022-01022-y
redox balance, ROS, glutathione and the need to balance cancer-cell vulnerability against potential normal-tissue toxicity.
Natural compounds and CSC metabolism
Therapeutic potential of natural compounds in targeting cancer stem cells: current evidence and future perspectives
Stem Cell Reviews and Reports. 2025.
https://doi.org/10.1007/s12672-025-03190-y
a broad review of compounds including curcumin, sulforaphane, berberine, EGCG, resveratrol and quercetin in CSC models; best used to document preclinical rationale, not clinical proof.Natural Compounds as Network-Level Modulators of Cancer Stem-Cell Plasticity: An Evidence-Weighted Review
Drugs and Drug Candidates. 2026.
https://www.mdpi.com/2413-4155/8/7/150
a current discussion of curcumin, sulforaphane, resveratrol, EGCG, berberine and quercetin as multi-target compounds affecting CSC plasticity. It is useful for mechanism mapping but should be paired with clinical-evidence and safety sources.Physiological Modulation of Cancer Stem Cells by Natural Compounds: Mechanisms, Evidence and Translational Challenges
https://www.sciencedirect.com/science/article/pii/S2950199725003039
the translational caution: natural-compound evidence is often preclinical, with challenges involving bioavailability, dosing, tumour heterogeneity and clinical validation.
Repurposed medicines and metabolic drugs
Emerging Therapies in Cancer Metabolism
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00265-6
the overall landscape for repurposed and investigational metabolic approaches, including mitochondrial, glycolysis, glutamine and redox strategies.Targeting Cancer Metabolism in the Era of Precision Oncology
https://doi.org/10.1038/s41573-021-00339-6
why only a small number of metabolism-directed approaches have translated successfully, and why tumour-specific biomarker selection and combinations matter.Cancer stem cells and drug resistance in cancer: molecular mechanisms and therapeutic targets
https://doi.org/10.1186/s43556-026-00516-2
metformin as a mitochondrial-complex-I research strategy; dual glycolysis/OXPHOS inhibition; fatty-acid oxidation; glutamine; glutathione depletion; thioredoxin inhibition; and ferroptosis-related strategies.
Related
This information is for education only. It is not medical advice, diagnosis, or treatment. Please speak with a qualified clinician before making changes to care, medication, or supplement use.
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