Ketogenic and Calorie-Restricted Diets in Cancer: Molecular Mechanisms, Metabolic Vulnerabilities and Translational Evidence

Review scope and approach. This narrative review focuses on the biological interface between dietary energy/carbohydrate availability and tumor metabolic plasticity. Evidence is considered across mechanistic, preclinical and human clinical literature, with emphasis on molecular pathways, metabolic biomarkers, treatment interactions and nutritional safety. Because ketogenic diets, calorie restriction, fasting and fasting-mimicking diets are metabolically distinct, their evidence is interpreted separately rather than as interchangeable interventions.

Cancer is a heterogeneous group of diseases characterized by uncontrolled proliferation, genomic instability, altered signaling, immune evasion, invasion and metastatic potential. Increasing evidence indicates that metabolic reprogramming is an integral component of malignant transformation rather than merely a secondary consequence of rapid cell growth [1,2]. Cancer cells alter nutrient acquisition and utilization to generate ATP while simultaneously supplying the macromolecular precursors required for DNA, RNA, protein and membrane synthesis [2].

One of the best-known metabolic characteristics of cancer is the Warburg effect. Otto Warburg observed that many tumor cells consume large quantities of glucose and produce lactate even when oxygen is available [3]. This phenomenon is now understood as one component of a much broader metabolic reprogramming process. Importantly, contemporary cancer metabolism research has demonstrated that mitochondria remain functional in many tumors and that cancer cells can use both glycolytic and oxidative pathways depending on genetic, environmental and therapeutic conditions [4,5]. Therefore, the concept that all cancer cells are simply dependent on glycolysis is an oversimplification.

Nevertheless, altered glucose metabolism provides a potential therapeutic opportunity. Many tumors exhibit increased glucose uptake and enhanced expression of glycolytic enzymes, while oncogenic pathways such as PI3K/AKT/mTOR and MYC regulate nutrient acquisition and anabolic metabolism [2,5]. The relationship between glucose, insulin, IGF-1 and growth signaling has consequently stimulated interest in nutritional interventions that modify systemic metabolism.

Ketogenic diets and calorie restriction are two prominent dietary approaches investigated in this context. A ketogenic diet is characterized by severe carbohydrate restriction, relatively high fat intake and adequate protein, producing increased hepatic ketogenesis and circulating ketone bodies. In contrast, calorie restriction involves reducing overall energy intake without necessarily inducing nutritional deficiency. Fasting, intermittent fasting and fasting-mimicking diets represent related but distinct strategies [6,7].

The theoretical attraction of these approaches is based on the possibility that normal cells and malignant cells differ in metabolic flexibility. Normal tissues may adapt to reduced carbohydrate availability by increasing fatty-acid oxidation and ketone-body utilization, whereas selected tumors may be less capable of making the same metabolic transition [8]. However, this metabolic vulnerability is not universal and tumor heterogeneity represents a major limitation to the concept of a universal “cancer diet.”

The purpose of this review is to critically evaluate the impact of ketogenic and calorie-restricted diets on cancer metabolism, including their molecular mechanisms, preclinical evidence, clinical findings, potential interaction with cancer treatment, safety concerns and future research requirements.

Cancer Metabolism and the Warburg Effect

Normal cells use multiple metabolic pathways according to tissue requirements, oxygen availability and nutritional conditions. Glucose can undergo glycolysis to generate pyruvate, which may subsequently enter mitochondrial oxidative phosphorylation. Cancer cells frequently increase glucose uptake and glycolytic flux, resulting in substantial lactate production despite oxygen availability [3,4].

The Warburg effect may provide several advantages to rapidly proliferating cells. Although glycolysis produces less ATP per glucose molecule than complete mitochondrial oxidation, high glycolytic flux can rapidly provide energy while simultaneously generating intermediates for biosynthetic pathways. Glycolytic intermediates can contribute to nucleotide, amino-acid and lipid synthesis, while the pentose phosphate pathway generates NADPH and ribose-5-phosphate required for biosynthesis and redox regulation [4,5].

Cancer-associated metabolic reprogramming extends beyond glucose. Tumors can alter glutamine metabolism, fatty-acid synthesis, fatty-acid oxidation, mitochondrial respiration, one-carbon metabolism and amino-acid utilization [2]. Consequently, the metabolic phenotype of an individual tumor depends on its genetic alterations, tissue of origin, microenvironment, oxygenation, nutrient availability and treatment history.

This heterogeneity is important when considering dietary intervention. A glucose-restricted strategy may theoretically affect a highly glycolytic tumor differently from a tumor that relies extensively on oxidative phosphorylation or fatty-acid metabolism.

The emerging view is therefore that cancer metabolism consists of interconnected and adaptable networks rather than one abnormal pathway [2,4] (Table 1).

Table 1: Major Metabolic Alterations in Cancer and Potential Nutritional Implications

Biological Rationale for Ketogenic Diets

A ketogenic diet substantially reduces carbohydrate intake and increases fat availability. Low carbohydrate availability reduces insulin secretion and promotes lipolysis and hepatic ketogenesis. The liver produces ketone bodies, principally β-hydroxybutyrate and acetoacetate, which can be utilized as alternative energy substrates by several normal tissues [6,9].

The proposed anticancer rationale is that normal cells may maintain energy production through fatty-acid oxidation and ketone-body utilization, whereas some malignant cells may have limited metabolic flexibility. Consequently, carbohydrate restriction could theoretically increase metabolic stress in susceptible tumors [8,9].

However, this hypothesis should be interpreted cautiously. Cancer cells are not universally unable to metabolize ketone bodies. Some tumors retain considerable mitochondrial function and can use alternative carbon sources. Contemporary reviews emphasize that the metabolic response to ketogenic diets is highly context-dependent [4,10].

A ketogenic diet may also influence cancer biology through insulin and IGF-1 signaling. Reduced carbohydrate intake can decrease insulin concentrations, potentially reducing downstream signaling through PI3K/AKT/mTOR [10,11]. These pathways regulate proliferation, protein synthesis, cellular survival and metabolism.

Other proposed mechanisms include changes in oxidative stress, mitochondrial metabolism, reactive oxygen species, inflammation, angiogenesis and epigenetic regulation [10,12].

Although these mechanisms are biologically plausible, they should not be equated with proven clinical antitumor activity (Table 2).

Table 2: Proposed Mechanisms of Ketogenic Diets in Cancer

.

Calorie Restriction and Cancer Metabolism

Calorie restriction reduces total energy intake while maintaining adequate nutritional quality. Experimental studies have associated calorie restriction with reduced tumor incidence and altered tumor progression through multiple pathways [13,14].

One important mechanism involves the insulin/IGF-1 axis. Reduced energy intake may decrease insulin and IGF-1 signaling, which can influence PI3K/AKT/mTOR pathways involved in cell growth and survival [13,14]. Calorie restriction can also activate AMPK, an energy sensor that responds to reduced cellular energy availability. AMPK activation can suppress anabolic processes and inhibit mTOR signaling.

The mTOR pathway integrates information concerning nutrients, growth factors and cellular energy. Persistent mTOR activation promotes protein synthesis, cell growth and proliferation. Conversely, reduced nutrient availability can decrease mTOR activity and facilitate autophagy [13,14].

Autophagy is a cellular recycling process that removes damaged organelles and macromolecules. Its role in cancer is complex because it may suppress tumor initiation while also helping established tumors survive metabolic stress [14].

Calorie restriction may additionally influence oxidative stress, mitochondrial function, inflammation, immune responses and cellular stress resistance [6,13] (Table 3).

Table 3: Potential Effects of Calorie Restriction

.

Ketogenic Diet Versus Calorie Restriction

Ketogenic diets and calorie restriction should not be regarded as interchangeable interventions.

An isocaloric ketogenic diet changes the composition of macronutrients while maintaining energy intake. Calorie restriction decreases total energy intake regardless of macronutrient composition.

This distinction is critical because a patient following a ketogenic diet may spontaneously consume fewer calories. Therefore, an observed reduction in tumor growth or body weight may result from energy restriction rather than ketosis itself (Table 4).

Table 4: Comparison of Ketogenic and Calorie-Restricted Diets

Preclinical Evidence

The majority of mechanistic evidence supporting dietary metabolic interventions originates from cell culture and animal studies.

Preclinical studies have reported that ketogenic diets can slow tumor growth in selected models, particularly when combined with chemotherapy, radiotherapy, antiangiogenic therapy, or other metabolic interventions [10,12]. Proposed explanations include reduced glucose and insulin signaling, increased metabolic stress, altered redox balance and increased susceptibility to oxidative damage.

Similarly, calorie restriction and fasting have demonstrated antitumor effects in several animal models. These interventions may reduce IGF-1 and insulin signaling and alter stress-response pathways [6,13].

Fasting-related strategies have also attracted interest because they may create a temporary metabolic environment in which normal cells become more resistant to stress while tumor cells remain vulnerable. Longo and Mattson described this concept as differential stress resistance [6].

Experimental work has further suggested that fasting-mimicking diets may influence immune-mediated tumor destruction. Di Biase et al. reported that fasting-mimicking diet cycles combined with chemotherapy increased cytotoxic CD8+ tumor-infiltrating lymphocytes in experimental models and delayed tumor progression [16].

Similarly, a clinical/translational fasting-mimicking diet study demonstrated changes in metabolic and growth-related biomarkers, supporting further investigation of fasting-related approaches [17].

However, animal models cannot fully reproduce human cancer heterogeneity, nutritional status, treatment schedules, or cachexia. Therefore, positive preclinical findings require confirmation in adequately powered clinical trials.

Clinical Evidence for Ketogenic Diets

Clinical evidence concerning ketogenic diets has expanded considerably, but it remains heterogeneous.

An early systematic review concluded that evidence supporting isocaloric ketogenic diets for cancer treatment was insufficient, particularly because studies were small and varied substantially in design and cancer type [18].

Römer et al. subsequently reviewed 39 studies involving 770 patients and found no conclusive evidence that ketogenic diets improved tumor control or overall survival. They also identified important concerns regarding adherence, weight loss, adverse effects and methodological quality [19].

These findings are important because many early reports of ketogenic diets in cancer consisted of case reports, small pilot studies, uncontrolled studies, or highly selected populations. Such studies can demonstrate feasibility and biological effects but cannot establish clinical efficacy.

More recent randomized evidence provides a similarly cautious conclusion. Salido-Bueno et al. identified eight randomized controlled trials and found that ketogenic diets significantly reduced glucose but did not significantly improve cholesterol, IGF-1, weight, or quality of life [15].

A more recent systematic review and meta-analysis published in 2025 reported improvements in several metabolic and patient-reported outcomes, including glucose, insulin, fat mass, fatigue and insomnia, although the authors also emphasized differences in intervention characteristics and outcome measures [20].

These apparently different conclusions highlight the importance of distinguishing metabolic effects from oncological outcomes. A diet may improve glucose or insulin without necessarily reducing tumor progression or increasing survival.

The National Cancer Institute similarly notes that ketogenic diets are being studied in cancer but that their effectiveness for cancer control remains uncertain [21] (Table 5).

Table 5. Summary of Important Evidence

Ketogenic Diets and Conventional Cancer Treatment

A major research question is whether ketogenic diets can enhance chemotherapy, radiotherapy, targeted therapy, or immunotherapy.

The rationale is based on the possibility that metabolic stress may make cancer cells more vulnerable to conventional treatment. Reduced insulin/IGF-1 signaling and altered redox metabolism could theoretically increase treatment sensitivity [10,12].

Some preclinical studies have reported enhanced effects when ketogenic diets are combined with chemotherapy or radiation [10,12]. However, these findings are not sufficient to recommend dietary therapy clinically.

The combination of dietary intervention with immunotherapy is also of interest. Cancer cells compete with immune cells for nutrients within the tumor microenvironment. Changes in glucose, fatty acids, ketones and amino acids could theoretically influence both tumor cells and immune-cell function.

This creates a major challenge: a metabolic intervention designed to stress tumor cells must not compromise the nutritional and immune requirements of the patient.

Consequently, dietary intervention should be considered an adjunctive strategy rather than an alternative to established cancer treatment.

Calorie Restriction, Fasting and Fasting-Mimicking Diets

Calorie restriction, intermittent fasting, prolonged fasting and fasting-mimicking diets have overlapping but distinct metabolic effects.

Fasting reduces glucose, insulin and IGF-1 while increasing ketone bodies and activating cellular stress responses [6]. Longo and Mattson described fasting as a metabolic intervention capable of altering oxidative stress, inflammation, energy metabolism and cellular protection [6].

Calorie restriction has also been proposed as a strategy for improving cancer-treatment response. Preclinical evidence suggests that energy restriction may sensitize tumor cells to chemotherapy while enhancing stress resistance in normal cells [13,14].

Fasting-mimicking diets attempt to produce some of the biochemical effects of fasting while allowing limited food intake. Wei et al. demonstrated that repeated fasting-mimicking diet cycles influenced metabolic and aging-related biomarkers in humans [17].

Experimental cancer studies have reported encouraging results. Di Biase et al. found that fasting-mimicking diet combined with chemotherapy increased tumor-infiltrating cytotoxic T cells and delayed tumor progression in experimental breast cancer and melanoma models [16].

Nevertheless, fasting-related approaches may be inappropriate for patients with significant malnutrition, cachexia, low body mass, uncontrolled diabetes, or other conditions requiring consistent nutritional intake.

Nutritional Risks in Cancer Patients

One of the most important considerations in nutritional oncology is that cancer patients are not metabolically identical to healthy individuals.

Cancer-associated malnutrition can result from inadequate intake, inflammation, altered metabolism, treatment toxicity, gastrointestinal dysfunction and increased energy requirements. Progressive loss of skeletal muscle is associated with reduced physical function and poorer treatment tolerance.

Therefore, a dietary intervention that produces substantial weight loss may be harmful in a patient who is already losing muscle.

Potential complications of overly restrictive diets include:

• Excessive Weight Loss
• Skeletal Muscle Depletion
• Protein Inadequacy
• Micronutrient Deficiency
• Dehydration
• Gastrointestinal symptoms
• Reduced treatment tolerance
• Poor adherence
• Worsening cachexia

The goal of nutritional intervention should therefore be metabolic optimization without compromising nutritional status (Table 6).

Table 6: Potential Benefits and Risks of Metabolic Diets

.

Tumor Heterogeneity and Metabolic Flexibility

A central limitation of the ketogenic-diet hypothesis is that cancer is metabolically heterogeneous.

Some tumors display high glycolytic activity, whereas others maintain substantial oxidative phosphorylation. Cancer cells can also adapt their metabolism according to oxygen, nutrient availability, genetic alterations and interactions with stromal cells [2,4].

The tumor microenvironment further complicates this picture. Cancer-associated fibroblasts, endothelial cells, immune cells and malignant cells exchange metabolites and influence each other’s metabolic behavior.

Consequently, a universal recommendation that all cancer patients should follow a ketogenic or calorie-restricted diet is not supported by current evidence.

Future nutritional oncology may instead involve metabolic phenotyping. Potential biomarkers could include glucose uptake, lactate production, mitochondrial activity, expression of metabolic enzymes, insulin/IGF-1 signaling, ketone-body utilization and tumor genomic characteristics (Table 7).

Table 7: Potential Biomarkers for Precision Nutritional Oncology

.