The clinical problem the review addresses is stark. Although surgery, platinum-taxane chemotherapy, and newer maintenance strategies such as PARP inhibitors have improved outcomes in recent years, most patients are diagnosed at an advanced stage, and recurrent tumors frequently acquire resistance to the very drugs that initially controlled the disease. Classical explanations of chemoresistance have focused on enhanced DNA repair capacity, reduced intracellular drug accumulation, evasion of apoptosis, and the plasticity that allows tumor cells to shift between epithelial and other states. What makes this review distinctive is its argument that each of these classical mechanisms is increasingly inseparable from metabolic adaptation. DNA repair consumes ATP and NAD⁺; apoptosis evasion depends on antioxidant capacity and lipid signaling; cell plasticity is fueled by shifts in substrate preference. Metabolism, in other words, is not a bystander in resistance—it is an active enabler.

At the center of the metabolic argument is the balance between glycolysis and mitochondrial oxidative phosphorylation. The review details how, under therapeutic pressure, subsets of ovarian cancer cells shift toward a glycolysis-dominant state, upregulating key enzymes and transporters such as hexokinase 2 (HK2), phosphoglycerate kinase 1 (PGK1), phosphoglycerate mutase 1 (PGAM1), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and monocarboxylate transporters, particularly MCT4. This Warburg-like configuration allows cells to generate ATP rapidly and to channel glycolytic intermediates into biosynthetic pathways that support survival, while the export of lactate acidifies the tumor microenvironment and can impair the activity and penetration of chemotherapeutic agents. The hypoxia-inducible factor HIF-1α emerges as a central transcriptional driver of this program, linking low oxygen conditions commonly found in advanced ovarian tumors to both glycolytic switch and chemotherapy failure.

Importantly, the authors emphasize that glycolysis is not the whole story. Other resistant tumors instead become dependent on mitochondria, relying on oxidative phosphorylation and the tricarboxylic acid cycle to sustain their energy demands. In these mitochondria-dependent states, glutamine metabolism becomes critical: the enzyme glutaminase (GLS) feeds glutamine-derived carbon into the TCA cycle, while glutamic pyruvate transaminase 2 (GPT2) supports anabolic and redox needs. This bidirectional plasticity—some cells abandoning respiration while others deepen their reliance on it—helps explain why single-agent metabolic inhibitors have often disappointed in the clinic. A drug that blocks glycolysis may spare a mitochondrial subpopulation, and vice versa, allowing residual cells to repopulate the tumor. The review argues that mapping which metabolic state dominates in a given patient’s tumor at a given time could be essential to choosing the right metabolic vulnerability to target.

Perhaps the most vivid section of the review concerns lipid metabolism, an area that has gained traction in ovarian cancer research partly because of the disease’s characteristic pattern of peritoneal and omental spread. Ovarian cancer cells floating in ascites or colonizing fatty omental tissue are surrounded by an environment rich in lipids, and resistant cells appear to exploit this bounty. The review describes upregulation of the fatty acid transporter CD36 and fatty acid binding protein 4 (FABP4), which enhance uptake of exogenous fatty acids, alongside increased expression of fatty acid synthase (FASN) for endogenous lipid production. Downstream, enzymes such as stearoyl-CoA desaturase 1 (SCD1), squalene epoxidase (SQLE), and HMG-CoA reductase (HMGCR)—the latter under the control of the sterol regulatory element-binding protein SREBP2—reshape the lipid composition of cellular membranes. These lipid adaptations do more than supply energy: they maintain membrane integrity against drug-induced damage, alter signaling through lipid-modified proteins, and buffer cells against the oxidative stress that platinum agents generate.

This lipid remodeling connects directly to one of the most discussed topics in modern cancer biology: ferroptosis, an iron-dependent form of cell death driven by the accumulation of lipid peroxides in cellular membranes. Chemotherapy generates reactive oxygen species, and ferroptosis represents a vulnerability that many tumors actively suppress. The review outlines the central defensive axis built around the cystine importer SLC7A11 and glutathione peroxidase 4 (GPX4), which together import cystine, generate glutathione (GSH), and enzymatically repair oxidized membrane lipids. A second, GPX4-independent shield is provided by ferroptosis suppressor protein 1 (FSP1), which reduces coenzyme Q10 at the plasma membrane using NADPH. The acyl-CoA synthetase ACSL4 also features prominently, because it determines which fatty acids are incorporated into membranes and therefore how susceptible a cell is to lipid peroxidation in the first place. Resistant ovarian cancer cells, the authors argue, frequently display a ferroptosis-resistant profile characterized by high antioxidant capacity and altered membrane lipid composition, effectively rendering them invisible to a form of cell death that chemotherapy might otherwise induce.

Adding a genuinely novel dimension, the review devotes substantial attention to cuproptosis, a recently described form of regulated cell death triggered by copper-dependent toxicity. Unlike ferroptosis, cuproptosis does not depend on lipid peroxidation; instead, excess copper promotes the aggregation of lipoylated mitochondrial enzymes, principally dihydrolipoamide S-acetyltransferase (DLAT), disrupting respiration and causing proteotoxic stress. The machinery of protein lipoylation—lipoic acid synthase (LIAS) and lipoyltransferase 1 (LIPT1)—and the copper-transporting ATPases ATP7A and ATP7B, along with the copper transporter CTR1 (SLC31A1) and the mitochondrial protein ferredoxin 1 (FDX1), all modulate sensitivity to this pathway. The review suggests that certain ovarian cancer subtypes, particularly those with high mitochondrial lipoylation, may be inherently cuproptosis-sensitive, raising the possibility of copper ionophores or copper-mobilizing strategies as a way to kill tumors that have survived conventional therapy. Intriguingly, CTR1 is also implicated in cisplatin uptake, linking copper biology directly to platinum drug transport.

A recurring theme throughout the review is dynamism. Resistant tumors are portrayed not as uniformly glycolytic or uniformly mitochondrial, but as ecosystems in which distinct metabolic and cell-death states—glycolysis-dominant, mitochondria-dependent, lipid-adapted, ferroptosis-resistant, or cuproptosis-sensitive—coexist and shift over time in response to chemotherapy, recurrence, and microenvironmental selection pressures such as hypoxia and lipid availability. A tumor sampled at diagnosis may present a very different metabolic face from the same tumor after six cycles of carboplatin and paclitaxel. This temporal evolution explains both why initial biopsies have limited predictive power and why static biomarker studies of metabolic genes have produced inconsistent results. The authors advocate for serial metabolic characterization of tumors, potentially using non-invasive imaging or liquid biopsy approaches, as a foundation for treatment selection.

The therapeutic implications are considerable, and the review is careful to frame them as biologically informed strategies rather than ready-made protocols. Combination approaches emerge as the logical consequence of the model: pairing a metabolic inhibitor matched to the dominant resistance state with chemotherapy or with agents that collapse specific antioxidant defenses. For glycolysis-dominant tumors, targeting HK2, LDHA, or lactate export might resensitize cells to platinum; for mitochondria-dependent tumors, inhibition of GLS or respiratory complexes could be preferable; for lipid-adapted tumors, blocking CD36, FASN, or SCD1 might strip away a critical survival layer. In parallel, inducing ferroptosis by inhibiting SLC7A11 or GPX4 could be combined with chemotherapy to convert a hidden stress into lethal damage, while cuproptosis-sensitizing strategies could open an entirely orthogonal cell-death route untouchable by existing resistance mechanisms. The unifying principle is that the choice of metabolic target should be dictated by the tumor’s measured metabolic state, moving treatment design away from broadly applied combinations toward rational, individualized regimens.

As a review, the article does not present new experimental data, and the authors acknowledge that much of the evidence comes from cell lines, xenografts, and retrospective biomarker analyses; translating metabolic profiling into validated clinical decision tools will require prospective studies and, ultimately, biomarker-guided clinical trials. Funding was provided by the Proof of Concept Project of Fudan University Huashan Hospital and the Yangfan Plan of the Shanghai Science and Technology Commission. Nevertheless, the synthesis arrives at a timely moment, as ferroptosis-targeting compounds and several metabolic inhibitors progress toward and through early-phase clinical testing across oncology. For a disease in which the median survival for advanced-stage patients has improved only incrementally over decades, the message that chemoresistance is a tractable metabolic problem—one with concrete molecular nodes, measurable states, and emerging pharmacological tools—offers a coherent roadmap for the next generation of ovarian cancer research. The challenge now, the authors imply, is not to find one more drug, but to learn to read the tumor’s metabolic handwriting and strike where it is most vulnerable.

The authors of this groundbreaking study emphasize that cancer cells exhibit a unique metabolic profile that prioritizes glucose uptake and utilization. This phenomenon, known as the Warburg effect, highlights the preference of cancer cells for glycolysis over oxidative phosphorylation, even in the presence of adequate oxygen. Understanding this metabolic alteration is essential because it not only underscores the inherent differences between malignant and normal cells but also paves the way for targeted therapies that disrupt this glycolytic dependency.

Moreover, the research sheds light on how altered glucose metabolism can also influence immune responses. The role of metabolic pathways in shaping the functionality of immune cells is increasingly recognized, adding another layer of complexity to the relationship between metabolism and disease. For instance, the authors provide evidence that high glucose levels can dampen the immune response, creating a conducive environment for tumor progression. This regulation of immune cells by glucose metabolism presents a potential target for therapeutic modulation and could lead to improved outcomes in cancer treatment.

The findings also highlight the importance of tumor microenvironments. The metabolic state of cells within a tumor can greatly affect the surrounding immune landscape. By studying how glucose metabolism interacts with immune cells, the researchers point to opportunities for combination therapies that can both target cancer cells and modulate the immune response. This dual approach could enhance the efficacy of existing treatments, which often suffer from limitations due to the tumor’s ability to evade the immune system.

Additionally, the article discusses various strategies to exploit glucose metabolism for cancer therapy. One compelling avenue is the use of glucose analogs and other metabolic inhibitors that can selectively target cancer cells. These agents could disrupt the glycolytic pathways that are so critical for tumor growth while sparing normal tissues that do not rely on these pathways to the same extent. This targeted metabolic disruption presents a promising strategy that could improve patient outcomes significantly.

Importantly, the researchers offer insights into the challenges that lie ahead in the quest for metabolic targeting. While the promise of glucose metabolism as a therapeutic target is enticing, there are numerous hurdles, including the potential for resistance and the need to balance efficacy with toxicity. The complexity of metabolic pathways necessitates a comprehensive understanding of metabolic plasticity in tumors, and ongoing research will be vital to navigate these challenges.

As the field progresses, it becomes increasingly clear that a multidisciplinary approach will be essential. The convergence of metabolism, immunology, and cancer biology suggests that collaborations among various scientific disciplines could yield transformative insights and enhance the development of novel interventions. For example, integrating metabolic profiling with immunotherapy could provide a clearer picture of how to manipulate tumor metabolism to favor immune activation.

The implications of this research extend beyond cancer alone. Glucose metabolism plays a vital role in various diseases, and understanding its regulation could have far-reaching effects on public health. Metabolic disorders, such as diabetes and obesity, share overlapping pathways with cancer, and the lessons learned from cancer research could inform strategies for managing these prevalent conditions.

Furthermore, the article encourages researchers to explore the therapeutic potential of dietary interventions. Nutritional modulation may provide an accessible and non-invasive method to impact glucose metabolism and, consequently, both cancer progression and immune regulation. Creating dietary strategies designed to manipulate glucose levels could serve as an adjunct to standard cancer therapies, ultimately leading to improved survival rates.

As research continues to unfold, it will be important to translate laboratory findings into clinical applications. The journey from bench to bedside often involves rigorous testing and validation, and the authors highlight the necessity for clinical trials tailored to evaluate metabolic interventions. Success in this arena could establish a new paradigm in cancer treatment that prioritizes the metabolic profiles of tumors.

In conclusion, the exploration of glucose metabolism as a target for cancer and immune regulation opens up new frontiers in biomedical science. The synergy between diet, metabolism, and immune function is becoming increasingly apparent, marking a shift towards a more integrated understanding of health and disease. As researchers continue to unravel the complexities of glucose metabolism, the potential for novel therapies looms large, promising hope to patients and transforming the landscape of cancer treatment.

Ultimately, the future of cancer therapy may reside in understanding and manipulating metabolic pathways to not only starve tumors but also re-energize the immune system to fight them effectively. As we stand on the brink of a new era in cancer research, the findings of Pan, Hsu, and Wu will undoubtedly inspire further studies that could lead to revolutionary therapeutic strategies.

Subject of Research: The relationship between glucose metabolism, cancer biology, and immune regulation.

Article Title: Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.

Article References:

Pan, BS., Hsu, CC., Wu, HE. et al. Glucose metabolism and its direct action in cancer and immune regulation: opportunities and challenges for metabolic targeting.
J Biomed Sci 32, 71 (2025). https://doi.org/10.1186/s12929-025-01167-1

Image Credits: AI Generated

DOI: https://doi.org/10.1186/s12929-025-01167-1

Keywords: Glucose metabolism, cancer, immune regulation, metabolic targeting, Warburg effect, therapeutic strategies.