Ketogenic Diet: A Metabolic Key to Overcoming Cancer Therapy Resistance

ABSTRACT

The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein consumption, and variable fat content depending on the specific dietary protocol, has emerged as a promising metabolic approach in oncology. Although significant progress has been achieved in chemotherapy and immunotherapy for cancer treatment, it still faces challenges in terms of resistance to drugs, systemic toxicity, and immunosuppressive microenvironments of tumor tissues. The KD has been reported to exploit the metabolic weaknesses of tumor cells, such as glycolytic addiction and mitochondrial rigidity, while sparing normal tissue metabolism. The anticancer effects of KD are linked to metabolic and signaling reprogramming that may increase tumor sensitivity to treatment. The ketone bodies, especially β‐hydroxybutyrate, play a significant role in tumor metabolism and stress response through histone deacetylase inhibition, anti‐inflammatory properties in normal tissues, and modulation of chemotherapy‐induced toxicity. A large body of preclinical data supports the use of KD to enhance the efficacy of chemotherapeutic agents, such as cisplatin, doxorubicin, temozolomide, and gemcitabine, through mechanisms that include redox imbalance, inhibition of DNA repair, and induction of apoptosis in tumor cells. Emerging experimental data also indicate that KD may affect the tumor immune microenvironment by modulating effector and suppressive immune cells and by interacting with immune checkpoint therapy. However, the translation of these data into the clinic is heterogeneous. Early‐phase clinical trials and feasibility studies in glioblastoma, breast, colorectal, and pancreatic cancers have shown that KD is feasible in the clinic and that some benefits in metabolic parameters and quality of life are observed, but evidence of anticancer activity remains limited. Importantly, the response to KD in the clinic seems to depend on the formulation and implementation of the dietary intervention, including the use of high‐fat KDs versus very‐low‐calorie ketogenic diets (VLCKDs), as well as the metabolic context in which the intervention is performed, including obesity and insulin resistance. Overall, current data support KD as a biologically plausible and hypothesis‐generating immunometabolic strategy that warrants further evaluation in well‐designed, controlled clinical trials with careful attention to dietary composition, metabolic phenotype, safety, and patient adherence.

The ketogenic diet induces β‐hydroxybutyrate production, triggering metabolic reprogramming, increased susceptibility to chemotherapy and immunotherapy, and favorable immune modulation. These coordinated effects target multiple mechanisms of cancer therapy resistance, potentially improving treatment efficacy, metabolic health, and patient outcomes while supporting future precision nutritional strategies.

1. Introduction

Cancer is one of the top causes of morbidity and mortality in the world. The branch of medicine that deals with cancer, clinical oncology, has to face new challenges as patients develop resistance to treatment and suffer from systemic toxicity of new chemotherapy regimens, immunotherapy, and targeted treatments [1]. Cancer cells have completely transformed their metabolism, known as the Warburg effect, using aerobic glycolysis as their main energy source even when sufficient oxygen is available to support other energy pathways [2]. The body needs glucose and glutamine for metabolism, which provides a new treatment opportunity. The ketogenic diet (KD), defined by low carbohydrate content, moderate protein intake, and variable fat content, was initially intended for the management of epilepsy. Since then, researchers have been interested in its impact on other neurological and metabolic conditions [3]. In recent years, KD has attracted attention in oncology as a metabolic strategy that may influence tumor growth and treatment response. Ketone bodies, particularly β‐hydroxybutyrate, may contribute to the biological effects of KD through metabolic and signaling regulation [4].

The metabolic characteristics of cancer, which are characterized by glycolytic metabolism without metabolic flexibility, make them more susceptible to glucose deprivation, whereas normal cells can switch their energy sources from glucose to ketone bodies, thereby conferring differential stress resistance [5]. Preclinical studies have shown that treatment with KD, cisplatin, doxorubicin, and temozolomide increases cancer cell death while protecting normal body tissues from harmful side effects [6]. The ketone body BHB functions as an epigenetic agent that acts as a histone deacetylase HDAC inhibitor and NLRP3 inflammasome modulator to control gene expression and inflammatory processes that drive tumor development and treatment results [6].

KDs have been shown to play an important role in modulating mechanisms of the anticancer immune response. The tumor immune microenvironment undergoes major changes driven by tumor metabolism, leading to an immunosuppressive environment in which T cells are deprived of nutrients and become dysfunctional [7]. Recent studies have shown that ketogenic metabolism allows CD8 T‐cells to persist longer while maintaining their ability to fight cancer, decreases the growth of regulatory T‐cells, and may increase the success rate of immune checkpoint inhibitors, including anti‐PD‐1 and anti‐CTLA‐4 antibodies [8, 9]. The research shows that KD improves immunotherapy outcomes in murine tumor models, indicating that metabolic changes can work in concert with efforts to restore antitumor immunity [10]. Early‐phase clinical studies and case reports provide preliminary evidence of the feasibility and tolerability of KD in cancer patients, but robust, large‐scale clinical trials remain limited [11].

The capacity of ketogenic treatments to enhance tumor cell response to cytotoxic damage while altering host immune system functioning has attracted significant research interest for its possible application in combination cancer therapy development. The existing data supporting these effects have been obtained from preclinical studies and early clinical trials, which have provided only incomplete and inconsistent human data. Current evidence indicates that KDs have been used as an experimental metabolic therapy, which has not been proven for the treatment of cancer. There are various critical issues that have to be addressed, including the selection of the component of the diet and the duration of the treatment, the selection of patients who will benefit from the treatment based on their metabolic characteristics, the long‐term safety and patient compliance of the treatment, and the development of metabolic resistance of the tumors during continuous treatment with KDs. The purpose of this review is to summarize existing mechanistic studies, preclinical data, and clinical evidence to establish the efficacy of the KD as a chemotherapeutic and immunotherapeutic approach, while also highlighting the current hurdles and future directions of this metabolic therapy in cancer treatment.

2. KDs and Cancer Metabolism

2.1. KD and Types

The KD is defined by very low carbohydrate intake, moderate protein consumption, and a variable proportion of dietary fat depending on the specific dietary protocol (e.g., classical KD, modified KD, VLCKD, and so forth), rather than representing a uniformly high‐fat diet. This metabolic approach promotes the production of ketone bodies, including acetoacetate, β‐hydroxybutyrate, and acetone, through hepatic fatty acid oxidation. These ketone bodies are transported via the bloodstream to peripheral tissues, where they are converted into acetyl‐CoA and utilized as an alternative energy source in the tricarboxylic acid cycle. Due to carbohydrate restriction, KD may also improve glycemic control and reduce blood glucose levels [12, 13]. The macronutrient composition of KD varies considerably across different dietary strategies. While classical KDs typically follow a fat‐to‐carbohydrate plus protein ratio of 3:1 or 4:1, resulting in a high proportion of dietary fat, other variants involve different macronutrient distributions and caloric intake levels [12, 14]. Several forms of KD have been developed to improve feasibility and adherence, including the classical long‐chain triglyceride (LCT) KD, medium‐chain triglyceride (MCT) KD, low glycemic index treatment (LGIT), and the modified Atkins diet (MAD).

The classical LCT‐based KD is often difficult to maintain due to its restrictive nature and the complexity of preparation [15]. In contrast, MCT‐based diets provide greater dietary flexibility, as MCTs are more efficiently converted into ketone bodies and require lower total fat intake compared to LCT‐based diets [15, 16, 17]. However, MCT diets are frequently associated with gastrointestinal side effects [18]. As shown in Table S1, the MAD represents a less restrictive alternative, allowing greater flexibility in food selection without strict limitations on calorie, protein, or fluid intake [19]. Importantly, very‐low‐calorie ketogenic diets (VLCKDs) represent a distinct category and should not be considered equivalent to classical high‐fat KDs. VLCKDs induce nutritional ketosis primarily through severe carbohydrate and caloric restriction, combined with adequate protein intake to preserve lean body mass, often with lower overall fat content than traditional KD approaches [20, 21]. VLCKDs have been associated with pronounced reductions in insulin and insulin‐like growth factor‐1 (IGF‐1) levels, as well as rapid metabolic adaptations, including decreased body fat and reduced lipid‐associated metabolic stress [21]. A recent clinical study further demonstrated that VLCKD‐induced ketosis is associated with reductions in pro‐inflammatory cytokines, improvements in oxidative stress markers, and modulation of immune‐related pathways, providing direct evidence of its metabolic and immunological effects [22, 23]. Overall, KD should not be regarded as a single uniform dietary intervention but rather as a group of related metabolic strategies with distinct macronutrient compositions and physiological effects. These differences influence ketosis induction, metabolic regulation, treatment tolerability, and potential anticancer efficacy [14, 15]. Variations in fat sources, macronutrient proportions, and dietary structure further affect inflammation, immune response, and tumor‐related outcomes [20, 24, 25, 26]. The lack of standardization across KD protocols remains a major challenge in interpreting clinical and preclinical findings, highlighting the importance of precise dietary characterization when evaluating KD as a therapeutic strategy.

2.2. Mechanism of KDs

Under ketogenic conditions, carbohydrate intake is typically limited to <50 g/day (often <10% of total caloric intake), leading to depletion of hepatic glycogen stores and a consequent shift in systemic energy metabolism away from glucose dependence [20, 37]. In response, hepatic β‐oxidation of fatty acids is upregulated, resulting in the production of ketone bodies, primarily β‐hydroxybutyrate (BHB), acetoacetate, and acetone, which are released into the circulation and serve as alternative energy substrates for peripheral tissues [37, 38]. Healthy tissues such as skeletal muscle, cardiac muscle, and the brain are readily adaptable to this metabolic state by increasing ketone utilization and mitochondrial energy production, thereby maintaining energy balance despite limited glucose availability [5, 39]. Most tumor cells have very limited metabolic pathways, depending primarily on aerobic glycolysis; their ability to metabolize ketone bodies remains impaired. This type of cancer is the result of mitochondrial dysfunction and metabolic changes associated with malignancy [40, 41]. Restricting carbohydrates to tumors creates an energy deficit while maintaining energy levels in healthy tissue. The KD maintains moderate protein intake to support lean body mass and essential anabolic processes while preventing excessive stimulation of gluconeogenesis and insulin release, which would otherwise disrupt ketosis [20, 42]. The KD induces a metabolic shift from glucose dependence to ketone body utilization, allowing normal tissues to rely on oxidative metabolism for energy.

2.3. Advantages and Risks of KDs in Oncology

The KD has been proposed as a metabolic adjuvant in cancer therapy, particularly in the context of chemotherapy. This approach is partly based on the reliance of many tumor cells on aerobic glycolysis (Warburg effect), creating a metabolic vulnerability that may be exploited through dietary carbohydrate restriction. Its potential therapeutic effects are largely attributed to metabolic and redox reprogramming mechanisms. By altering tumor energy metabolism and increasing metabolic stress, KD may enhance tumor sensitivity to cytotoxic agents while preserving normal tissue function. However, the extent of this effect remains highly context‐dependent, varying across tumor types and clinical settings [43, 44, 45, 46]. The proposed metabolic advantage is limited in its applicability across cancer types because it depends on the cancer type, metabolic phenotype, and research conditions. The preclinical studies have shown that there is metabolic support for ketogenic therapies, but there are significant differences in the response to ketogenic therapies. The KD, when applied in combination with calorie restriction in experimental cancer models of systemic metastasis of gastric cancer, neuroblastoma, and glioma, resulted in reduced tumor growth by decreasing angiogenesis and increasing survival times [47, 48, 49, 50]. The experimental model of prostate cancer resulted in inconsistent outcomes, suggesting that different cancers respond variably to ketogenic metabolic stress based on their susceptibility to the treatment [51].

On the other hand, human data is associated with complex challenges that need in‐depth analysis before a clear meaning can be understood. On the other hand, evidence from early human clinical trials indicates that some patients experience tumor stabilization, improved quality of life, and enhanced survival while on a KD [52]. Some studies have indicated that KD does not provide significant clinical benefits to all patients, as it does not yield positive outcomes in all patients. The KEATING study, conducted in glioblastoma patients, assessed the feasibility of KD and found that patients experienced varying levels of engagement and tolerability, with those in ketosis having better health outcomes [53]. Clinical research has been conducted on breast cancer, ovarian cancer, and endometrial cancer patients, and improvements were observed in physical functions, metabolic markers, and quality of life through small‐scale research, though the research has limitations based on the short‐term intervention and different dietary approaches applied [54, 55, 56]. The evidence indicates that KD has positive outcomes in certain patients under specific criteria; however, the implications of KD in a medical setting require further research, and the plan includes investigating its impact on specific diseases.

Although the KD method has some advantages, many operational problems pose a threat to its implementation. Patients face difficulties in being fully compliant with the KD treatment, which requires them to undergo rigorous medical procedures such as chemotherapy and radiotherapy. Common short‐term side effects include gastrointestinal discomfort, fatigue, and flu‐like symptoms (often called the keto flu) [57]. Variations in tumor metabolism across cancer types indicate that each type will respond differently to KD treatment due to distinct glycolytic and ketolytic pathway enzyme expression and overall metabolic capacity. Recent preclinical studies have revealed safety issues that arise in specific circumstances because evidence exists that shows that KD treatment worsens cardiotoxic effects from chemotherapy drugs in doxorubicin breast cancer models [58]. Antioxidant supplements appear to reduce some of the harmful effects observed in the study [25]. The observation requires scientists to assess the potential therapeutic benefits against the corresponding risks of KD treatment.

Obesity acts as a primary factor that alters cancer risk and tumor development and treatment effectiveness, which defines the metabolic condition that requires assessment of ketogenic and low‐carbohydrate treatments. Obesity causes sustained high insulin levels and insulin resistance, which maintain active insulin/IGF‐1 signaling pathways, including PI3K/AKT/mTOR. These pathways enable tumors to grow and survive while they develop resistance to medical treatment [59, 60]. Excess body fat leads to a permanent mild inflammatory state, elevating pro‐inflammatory cytokines such as IL‐6 and TNF‐α and disrupting adipokine signaling, thereby increasing leptin production and decreasing adiponectin release. These changes create conditions that promote blood vessel formation and immune system suppression, thereby supporting tumor development [61, 62]. KDs, together with carbohydrate‐restricted diets, help stop obesity‐related mechanisms that drive tumor growth by decreasing blood insulin and IGF‐1 levels, lowering body‐wide inflammation, establishing proper adipokine levels, and enabling the body to regain metabolic flexibility [63, 64]. Research studies show that ketogenic treatments produce antitumor results that depend on the specific context of body fat distribution and metabolic characteristics. These characteristics include visceral fat, sarcopenic obesity, and baseline insulin resistance [65]. The mentioned results demonstrate that researchers must investigate the connection between keto diet effectiveness at treating cancer and people with different levels of obesity and different metabolic health statuses.

The studies summarized in Table S2 demonstrate both the potential of KD to treat various cancer types and its limitations across these cancer types. Animal models of malignant glioma exhibited higher β‐hydroxybutyrate levels and extended survival when researchers used a 4:1 fat, carbohydrate, protein ketogenic formula, which, when paired with whole‐brain radiation, kept tumors under control without recurrence over a long‐term observation period [66]. A corresponding clinical case report in a patient with glioblastoma multiforme showed metabolic changes and temporary tumor regression during a restricted KD, followed by tumor recurrence after diet discontinuation [67]. In breast cancer, randomized and controlled trials reported reductions in fasting glucose, increased ketone levels, favorable changes in body composition, and improved quality of life, with some studies suggesting survival benefit and others showing more modest or transient effects [68, 69, 70]. Preclinical work in colorectal and pancreatic cancer models demonstrated preserved muscle mass, reduced inflammatory markers, and reduced tumor burden under KD [71, 72]. Clinical studies in advanced and metastatic cancers generally found KD to be feasible and safe, with improvements in metabolic profiles and quality‐of‐life parameters, yet therapeutic responses varied and were not uniformly superior to standard care [54, 73, 74, 75, 76, 77, 78].

2.4. Integrated Mechanistic Axes of KD Action in Cancer

KDs induce a coordinated metabolic reprogramming that targets key oncogenic signaling and redox vulnerabilities in cancer cells. By restricting carbohydrate intake, KDs lower circulating glucose and insulin levels and suppress insulin‐like growth factor‐1 (IGF‐1) signaling, thereby attenuating activation of the PI3K/Akt/mTOR pathway, a central driver of tumor proliferation and survival in many cancers [84, 85, 86].

The KD has two primary actions on cellular metabolism: activation of AMP‐activated protein kinase (AMPK), which stimulates fatty acid oxidation and autophagy, and inhibits mTOR signaling. The metabolic changes result in increased cellular stress, which becomes increasingly evident in cancer cells [87, 88]. Moreover, the KD suppresses glycolytic flux and NADPH production, leading to redox imbalance and increased ROS levels, and reveals underlying mitochondrial dysfunction [6, 89]. This heightened oxidative stress makes cancer cells more sensitive to cytotoxic agents, thereby increasing sensitivity to radiotherapy and chemotherapeutic agents such as temozolomide, gemcitabine, and cisplatin [6, 90]. The induction of ketogenic metabolic pathways leads to stress responses that are common to normal and cancer cells. Cancer cells face metabolic limitations that prevent them from using ketone bodies, whereas normal cells can adapt their metabolism to use ketone bodies, thereby reducing their growth signaling pathways [5]. The mechanism of differential stress resistance enables normal cells to withstand oxidative and genotoxic stress during cancer treatment, while cancer cells remain vulnerable to such stress [91]. The initial clinical results show that patients who stick to a KD during their chemotherapy and radiotherapy will achieve better results and quality of life, as their metabolic differences will be in their favor [4].

In addition to its metabolic effects, the KD also modulates epigenetic control and the inflammatory response by producing ketone bodies, especially BHB. BHB is known to be an endogenous inhibitor of class I histone deacetylases (HDACs), thus increasing the transcription of antioxidant defense genes, mitochondrial biogenesis, and the cell's resistance to stress [92]. On the other hand, BHB inhibits NLRP3 inflammasome activation and reduces the secretion of pro‐inflammatory cytokines such as IL‐1β and IL‐18, thereby creating a less inflammatory environment [93]. The above findings thus establish the link between the metabolic effects of the KD and epigenetic control of the cell and their implications in the inflammatory response.

Following these changes in histone regulation, there is increasing evidence that KDs can influence epigenetic regulation via DNA methylation. This extends the epigenetic impact of dietary ketosis beyond histone remodeling alone [94]. In humans with obesity, clinical studies have demonstrated that VLCKDs alter DNA methylation across multiple pathways, including insulin signaling, inflammation, lipid metabolism, mitochondrial function, and cancer biology. Significantly, these epigenetic changes are concomitant with improvements in insulin sensitivity and metabolic health, suggesting they are not coincidental but are related to these parameters [95, 96]. Genome‐wide methylation studies have identified changes in the methylation status of several oncogenes and tumor suppressor genes, including CCND1, MAPK10, GLI2, and LAMC3. These studies suggest that VLCKD‐induced nutritional ketosis may counteract obesity‐related epigenetic changes that promote tumor biology, thereby linking improved metabolic health to cancer biology [97].

Experimental evidence also exists supporting the direct involvement of ketone bodies in epigenetics. Studies on breast cancer cell lines have shown that exposure to β‐hydroxybutyrate or a ketogenic‐like environment can lead to alterations in DNA methylation of genes that regulate cell cycle, apoptosis, and metabolism. These epigenetic modifications have been associated with decreased cell proliferation and altered DNMT expression, suggesting a functional link between the metabolic environment and gene expression [55, 98]. Notably, these DNA methylation changes are not indiscriminate but rather appear highly dependent on the underlying metabolic environment, including obesity, insulin resistance, and chronic inflammation, as well as on the specific ketogenic regimen employed [97]. In keeping with these ideas, epigenome‐wide studies of visceral adipose tissue have shown that obesity‐related cancers have a distinct DNA methylation profile, many of which may be at least partially reversed by improvements in metabolism and weight loss. Collectively, these data suggest an indirect yet biologically plausible mechanism by which KDs might modulate tumor biology by reprogramming obesity‐related epigenetics [99].

From a clinical perspective, the implementation of KD in oncology is still in the early stages of exploration and remains highly context‐dependent. Early‐phase clinical trials and feasibility studies indicate that KD implementation is feasible in selected patient populations and that the diets may offer supportive benefits in cancer treatment, including metabolic benefits, increased tolerance to cancer therapies, and improved quality of life alongside standard treatment approaches. However, there is still no convincing evidence of survival benefits with this treatment approach [100, 101]. The outcome of this treatment modality varies significantly depending on the type of cancer, the type of dietary formula, the treatment setting, and compliance with dietary regimens. The application of KD in cancer treatment is still considered experimental rather than a standard treatment modality. It has been recommended that the KD application in cancer treatment be considered in the context of cancer‐specific trials [73].

Overall, the metabolic, redox, epigenetic, and stress‐adaptive effects ascribed to KD form a cohesive model that outlines the possible role of this intervention in cancer therapy. Notably, these effects are context‐dependent and influenced by tumor metabolism, type of therapy, and/or type of dietary intervention. In summary, it is now evident that KD exerts its effects through multiple related pathways rather than a single mechanism of action. This underscores the need to conduct well‐designed studies that incorporate patient‐ and tumor‐specific metabolic and molecular characteristics.

3. KDs as Adjuvants in Chemotherapy

3.1. Potential Mechanisms of Synergy Between KD and Chemotherapy

In 2011, the first experience with KD during chemotherapy was reported by Schmidt et al. [52], who conducted a prospective observational study in 16 cancer patients with metastatic disease to assess the feasibility of using KDs in the metastatic setting. The study demonstrated the potential of using the KD in conjunction with chemotherapy, supporting further exploration of its role as an adjunct therapy [6]. It is proposed that the potential synergy between chemotherapy and the KD arises from fundamental metabolic differences between cancer and normal cells. Tumor cell response to the KD is determined by intrinsic metabolic characteristics, and glycolytic dependency, mitochondrial function, and ability to utilize ketones vary among cancers. Under these circumstances, cancer cells become sensitive to chemotherapy‐induced stress, which can modulate the efficacy of chemotherapy. One significant factor associated with this interaction is the response to chemotherapy‐induced DNA damage. Tumor cells depend on energy‐dependent repair mechanisms to cope with DNA damage; however, the metabolic limitations imposed by KD can affect the adaptive response, thereby making tumor cells more susceptible to treatment [65]. On the other hand, normal cells can adapt to stress conditions induced during treatment due to their metabolic flexibility [5]. This supports the idea that KD can make tumor cells more susceptible to chemotherapy while sparing normal cells. Ketone bodies, particularly BHB, can play an important role in the systemic effects of KD, particularly with their signaling and regulatory activities. In addition to providing energy, ketone bodies have been associated with the modulation of inflammatory responses, which can affect toxicity during treatment [92]. This suggests that KD may have a dual role in the context of chemotherapy, increasing the sensitivity of tumor cells to chemotherapy while increasing the metabolic stability of normal cells. Although this evidence remains largely preclinical and clinical, it suggests the promise of metabolic therapies such as KD in the context of chemotherapy [102].

3.2. Evidence From Preclinical and Clinical Studies

An increasing body of preclinical and clinical research has explored whether KD can influence responses to chemotherapy, although the results remain variable and highly context‐dependent. Several animal studies report enhanced antitumor activity when KD is combined with standard chemotherapeutic agents, but the magnitude of benefit differs across tumor types and experimental settings. For example, in lung cancer xenograft models, combining KD with cisplatin and radiotherapy increased oxidative stress within tumor cells and produced greater tumor regression than either treatment alone [6]. In glioblastoma models, KD, when combined with temozolomide, extended survival, believed to be due to disruption of mitochondrial function and inhibition of glycolytic compensation mechanisms [65]. Synergistic antitumor responses have also been observed when KD is combined with doxorubicin or 5‐fluorouracil in certain models of breast and colon cancer [103, 104]. However, these observations have been made in highly controlled preclinical models and may not accurately reflect the metabolic heterogeneity and adaptability of human cancer.

However, translating positive findings from preclinical studies into consistent clinical responses has been much more difficult. While case series and pilot studies have shown that KD can be safely introduced in selected patients with cancer, including those with advanced disease, clinical responses have been variable. For instance, Schmidt et al. [52] showed that of 16 patients with advanced malignancies, KD was well tolerated, with some patients experiencing improvements in quality of life, energy levels, and sleep quality, while others discontinued the diet due to logistical and lifestyle‐related difficulties. Similarly, individual case reports in glioblastoma and other malignancies have demonstrated stabilization of disease or slowing of progression when KD was administered concomitantly with chemotherapy [105], although these results are uncontrolled and prone to large degrees of selection bias. In a feasibility trial involving patients with glioblastoma, KD was administered concomitantly with standard chemoradiotherapy and was associated with tolerable toxicities, primarily mild gastrointestinal side effects and laboratory‐related lipid profile changes, although compliance was highly variable and not all patients maintained ketosis [106]. Although some patients reported improvements in treatment‐related symptoms such as nausea and fatigue, this was not consistently observed. The overall evidence therefore suggests that KD can be safely employed among patients with cancer under the close supervision of experienced clinicians and dietitians for specific durations [107]. However, some issues are also encountered with the implementation of KDs, which include the challenges of long‐term compliance, undesired weight loss, and electrolyte imbalance. The KD may also be contraindicated among patients with cancer cachexia, severe sarcopenia, renal or hepatic impairment, or those with histories of eating disorders. The selection of patients is therefore crucial and should be based on the metabolic phenotype, nutritional status, cancer type, and treatment setting, with obese or insulin‐resistant patients as the target population [108].

The studies described in Table S3 emphasize the potential and limitations of KD in combination with chemotherapy. In head and neck cancer, early clinical studies of a KetoCal‐mediated KD in combination with cisplatin and radiation therapy showed increased oxidative stress and tumor control. However, patient compliance with this regimen has been difficult to achieve, as a parallel phase I study showed that only 4 of 12 patients adhered to the KD regimen due to poor compliance, dose‐limiting toxicity, and moderate weight loss [109]. In lung cancer xenograft models, tumor growth and proliferation were inhibited by radiation therapy, with or without carboplatin, in combination [6]. However, similar studies in patients are not yet available. In non‐small cell lung and pancreatic cancers, preclinical studies showed enhanced radiosensitivity and improved survival when combined with cisplatin, gemcitabine, or 5‐fluorouracil. However, similar studies in patients were limited, as a phase I study showed poor patient compliance to this regimen [110].

More favorable outcomes have been reported in selected settings. In pancreatic cancer models, KD combined with nab‐paclitaxel, gemcitabine, and cisplatin altered tumor metabolism, induced redox stress, and markedly prolonged survival compared with chemotherapy alone [111]. Retrospective observational clinical studies in NSCLC and advanced gastric cancer combining KD with chemotherapy, modulated electro‐hyperthermia, and hyperbaric oxygen therapy reported encouraging response rates and prolonged survival, although these multimodal designs limit the attribution of benefit specifically to KD [103, 112]. The KETOCOMP trial in rectal cancer demonstrated feasibility and improvements in quality‐of‐life domains and metabolic biomarkers in the KD group compared with controls [75], yet oncologic endpoints were not the primary outcome. In breast cancer, evidence remains mixed: an ongoing large randomized trial is evaluating irinotecan with KD [107], whereas a smaller 12‐week study showed only transient improvements in quality of life without sustained benefit [79]. Notably, potential risks have also emerged. While preclinical studies demonstrate in resistant breast cancer models demonstrated strong synergy between KD and melatonin [113], other work combining KD with doxorubicin preserved antitumor efficacy but exacerbated cardiac injury, raising safety concerns despite partial mitigation with vitamin C supplementation [78]. Further evidence includes isolated case reports of complete remissions [114], as well as experimental evidence from neuroblastoma model systems [27]. Although these data are limited, they are still inadequate to suggest clinical applicability.

In total, the data suggest that KD potently enhances chemotherapy response in preclinical models of more than 15 different types of cancer and 800 patients, whereas the clinical data are limited and variable, with response rates modestly affected by adherence, design, and selection. Compliance, dietary sustainability, and potential toxicity remain major barriers to implementation. Consequently, KD should be regarded as an experimental, adjunctive metabolic strategy, best explored within controlled clinical trials and multimodal treatment frameworks rather than as a universally effective enhancement to chemotherapy.

4. KDs as Adjuvants in Immunotherapy

4.1. Impact on Immune Metabolism and Synergistic Effects With Checkpoint Inhibitors

For many years, chemotherapy and radiotherapy have been the mainstay of cancer treatment because of their ability to kill rapidly dividing cells. However, their lack of specificity often harms healthy tissues as well as cancer cells. Over the past decade, immunotherapy has emerged as a promising new approach in oncology. Unlike traditional treatments, immunotherapy harnesses the body's own defense system. It builds on the idea that our immune system is naturally equipped with surveillance mechanisms, primarily through NK cells as well as CD4+ and CD8+ T cells, that can recognize and eliminate abnormal cells before they develop into full‐blown cancers [118]. Immunotherapy has reshaped modern oncology and is now a first‐line treatment for several cancers, including lung cancer, melanoma, genitourinary malignancies, and selected rare tumors with a high mutational burden. Unlike traditional chemotherapy, immunotherapy harnesses the patient's immune system to recognize and eliminate cancer cells. Increasing evidence suggests that treatment responses may be influenced by dietary factors, in part through diet‐induced alterations in the gut microbiome, which plays a central role in regulating antitumor immune responses [119]. Central to immune surveillance are immune checkpoint pathways involving proteins such as cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) and programmed cell death protein 1 (PD‐1). These proteins are critical in regulating T cell response. CTLA4 is an inhibitory protein expressed by T cells that competes with CD28 for interaction with B7‐1 and B7‐2 on antigen‐presenting cells (APCs). CD28 interaction with B7‐1/B7‐2 is required for T cell activation; thus, when CTLA4 binds B7‐1/B7‐2 instead of CD28, it prevents T cell activation and downregulates the immune response. Similarly, PD‐1 is expressed on T cells, and when it binds the programmed death‐1 ligand (PD‐L) on APCs, it attenuates the intracellular signaling cascade initiated by CD28 priming, thereby downregulating the immune response [120].

Although breakthroughs in cancer treatment through immune checkpoint blockade (ICB) have not completely solved the issue, because patients today experience treatment relapses and face severe side effects, which diminish their quality of life. The standard therapies used in cancer treatment fail to produce substantial, enduring results in shrinking tumors. The medical field is developing new treatment methods that combine adjuvant therapies and immunotherapy with immune response monitoring to address this problem. The most critical barrier to cancer treatment is that tumor cells generate an immunosuppressive TME, which reduces the body's capacity to combat the illness [121]. These so‐called immunologically “cold” tumors require therapeutic reprogramming of the patient's immune system to recognize and eliminate cancer cells [122]. The current strategy for activating the latent antitumor immune response primarily involves immunotherapy. In ICB treatment, a strong CD8+ T cell response is elicited by inhibiting PD‐1, PD‐L1, CTLA‐4, and LAG‐3, leading to tumor cell killing and reduced tumor size [123].

The antitumor immune response is also affected by the metabolic microenvironment, since immune cells require sufficient nutrients for effective activation, proliferation, and survival. During early activation, CD8⁺ T cells rely mainly on glucose to satisfy their metabolic requirements; however, for sustained effector functions and memory, T cells must undergo metabolic conversion, switching from glycolysis to oxidative phosphorylation and fatty acid oxidation [124]. On the other hand, tumor cells exhibit high glucose uptake and lactate production, resulting in a nutrient‐depleted, acidic TME that suppresses T‐cell function and favors the growth of Tregs and MDSCs [125]. KD may reshape the tumor microenvironment by altering nutrient availability and immune cell metabolism [108]. In addition, BHB has been shown to exert signaling activity, inhibit histone deacetylation, and suppress the NLRP3 inflammasome, thereby reducing inflammatory exhaustion and enhancing T‐cell survival. In accordance with this, research has demonstrated that KD induces the persistence of CD8⁺ T cells and their cytotoxicity, as well as reduced Tregs and MDSCs in the TME, resulting in an activated antitumor immune response [126].

Immunometabolic repurposing is a critical consideration for the effectiveness of immune checkpoint inhibitors targeting PD‐1 and CTLA‐4, which are designed to reinvigorate exhausted T cells. In the TME, immunosuppressive microenvironments are characterized by restricted glucose availability, altered T cell metabolism, and reduced efficacy of immune checkpoint inhibitors. KD could address these challenges by providing alternative metabolic substrates, particularly ketone bodies, while reducing the number of immunosuppressive cells in the TME. Combining KD or ketone body supplements with PD‐1 inhibitors improved tumor regression and survival in preclinical models compared with monotherapies, accompanied by increased CD8+ T‐cell infiltration and reduced expression of exhaustion markers [9, 127]. Other metabolic therapies, such as fasting‐mimicking diets, have also been shown to enhance the effectiveness of checkpoint inhibitors by reducing immunosuppressive cytokine levels and restoring T cell cytotoxicity [128]. These findings collectively suggest that metabolic therapies such as KD may enhance the bioenergetics of immune cells and help overcome resistance to immunotherapy, providing a promising strategy in immuno‐oncology.

4.2. Preclinical and Clinical Evidence

The KD may have additional effects on biological systems, such as epigenetic mechanisms and the immune system [129]. The impact of the KD on antitumor immunity is also unclear, as most oncology clinical studies have not systematically examined immune‐related endpoints [130, 131]. The preclinical studies listed in Table S4 provide important insights into potential mechanisms but also indicate substantial variation in immune effects. In multiple mouse tumor models, KD inhibited tumor progression and potentiated the efficacy of PD‐1 inhibitors, thereby improving survival [126]. These effects are likely due to metabolic changes in immune cells, in which ketone bodies support CD8+ T‐cell function, and to the tumor microenvironment, which reduces the growth of immunosuppressive cells. The magnitude and nature of these immune effects vary by tumor type and experimental conditions, indicating that the KD's impact on immune activity is context‐dependent.

The translation of the KD's immunometabolic correlates into a tangible clinical benefit is in its infancy. Feasibility studies have demonstrated that the KD can be safely administered to cancer patients undergoing systemic therapy, although its role in modulating antitumor immunity remains unestablished. In a pilot study of patients with glioblastoma, the KD was administered concomitantly with standard chemoradiotherapy and was well tolerated. Although some patients showed stabilization of their disease and improvement in performance status, others experienced little benefit and discontinued the diet due to difficulties implementing it [106]. Observational studies have also suggested that KD can reduce systemic inflammation and improve metabolic profiles, thereby creating a more favorable environment for immune checkpoint therapy. Although these studies are indirect and primarily hypothesis‐generating, they are important for providing background on the therapy's action [51]. Several clinical trials are currently underway to assess the combination of the KD with immune checkpoint therapy in melanoma, glioblastoma, and other malignancies, although its clinical efficacy has not yet been established.

Preclinical studies demonstrate further illustrate both beneficial and detrimental immune effects of KD. In aggressive tumor models, KD or the ketone 3‐hydroxybutyrate (3HB) restored responsiveness to checkpoint blockade that was ineffective under standard dietary conditions by suppressing PD‐L1 upregulation on myeloid cells, expanding CXCR3⁺ T cells, and reshaping the gut microbiota, leading to T cell–dependent tumor growth delay [9]. KD monotherapy in colon and glioma models has been associated with increased CD8⁺ and CD4⁺ T‐cell infiltration, reduced FOXP3⁺ regulatory T cells, shifts toward Th1 cytokine profiles, downregulation of PD‐1/PD‐L1/CTLA‐4 signaling, increased NK cell infiltration, and prolonged survival [130, 131]. Similarly, pancreatic and colorectal cancer models demonstrated reduced lactate production, decreased myeloid‐derived suppressor cell (MDSC) frequencies, restoration of NK cytotoxicity, and polarization toward M1 macrophages, all of which correlated with reduced tumor burden and increased apoptosis [132, 133, 134].

At the same time, several studies highlight context‐dependent or adverse immune effects. In a colorectal liver metastasis model, KD impaired NK cell viability and function through metabolite‐mediated ferroptosis and modulation of the Nrf2 pathway, ultimately promoting metastatic progression unless Nrf2 signaling was therapeutically targeted [135]. These findings contrast with other colorectal cancer models in which KD or BHB reprogrammed tumor‐associated neutrophils toward an antitumor phenotype and suppressed pro‐carcinogenic transcriptional programs [136], underscoring the complexity and variability of KD immune interactions. The prostate cancer models that showed resistance to ICIs demonstrated that KD and exogenous ketones improved tumor immunogenicity by increasing MHC class I expression and altering the tumor microenvironment, thereby enhancing the effectiveness of combined PD‐1 and CTLA‐4 blockade with HDAC inhibitors [51, 137, 138]. The study required complete adaptive immunity to observe results, but the results did not show consistent patterns across different experimental models. The kidney cancer xenografts showed that KD improved outcomes with anti–PD‐L1 therapy, but the higher PD‐L1 levels induced by KD treatment demonstrate that KD impacts the immune system in both positive and negative ways [127].

The current scientific evidence shows that a KD combined with immunotherapy helps specific patients maintain their disease under control for advanced colorectal cancer while also enhancing their quality of life [139]. Preclinical studies demonstrate that the KD or beta‐hydroxybutyrate enhances the efficacy of targeted therapies, including lenvatinib, for the treatment of hepatocellular carcinoma by inducing oxidative stress and inhibiting tumor growth [140]. The metabolic drugs and chemotherapy demonstrate their ability to work together with these substances because they decrease pancreatic ductal adenocarcinoma and triple‐negative breast cancer tumors [141, 142]. The research results are mostly preclinical studies that require careful evaluation.

The evidence presented in Table S4 demonstrates that KD affects the tumor immune microenvironment by improving antigen presentation and immune response, but yields mixed results: some cases show positive outcomes, while others show neutral or harmful outcomes, including increased metastatic spread. Overall, the conflicting results suggest that the KD does not exhibit uniform immunostimulatory activity and that its impact on immunotherapy efficacy depends on tumor type. Future research should focus on the KD as a metabolic adjuvant in a hypothesis‐driven manner, incorporating both mechanistic and well‐designed clinical studies. This will be crucial in determining when and how the KD can be used in combination with immunotherapies in different populations of patients.

5. Benefits and Opportunities

5.1. Potential for Improved Therapeutic Outcomes

The KD has thus been shown to regulate tumor metabolic processes and to help accurately measure treatment responses, making it a major advantage in oncological research. Cancer cells rely on glycolysis, which occurs aerobically through the Warburg effect, as this metabolic pathway becomes their only source of energy [39]. KD‐induced metabolic changes reduce glycolytic activity and may influence tumor‐associated signaling pathways involved in cancer progression [6]. Preclinical evidence suggests that the KD sensitizes tumor cells to cisplatin, temozolomide, and doxorubicin by increasing oxidative stress and decreasing DNA repair capacity [113, 146, 147]. Because of mitochondrial defects, tumor cells have developed resistance to stress and are now unable to use hydroxybutyrate and other ketone bodies for energy production [148]. Physicians now have a broader range of conventional therapies thanks to the very defect of this mechanism, and, at the same time, KD has been demonstrated to be a powerful adjunct therapy to chemotherapy and immunotherapy, thereby increasing patients' survival rates.

5.2. Enhanced Patient Quality of Life (Weight Management and Cachexia Reduction)

The cancer‐related syndrome cachexia, which causes weight loss, muscle degradation, and metabolic disorders, occurs in 80% of patients with advanced cancer [149]. Cachexia leads to patients being unable to tolerate treatments, and thus, it is one of the causes of death in these patients. In line with this, the KD has proven to be an effective treatment for cachexia as it is very high in fat and energy, dense, which allows patients to meet their calories requirements even when their appetite is low [150]. The KD stabilizes weight by regulating insulin and promoting fat utilization, leading to lower rates of catabolism. Clinical trials suggest that cancer patients who adopted KD had greater physical function, less fatigue, and better overall health [52]. The diet also allows obese patients who are undergoing treatment to regulate their weight because KD aids in maintaining metabolic flexibility and controlling blood glucose levels while at the same time reducing the symptoms of metabolic syndrome that typically get worse during systemic therapy [79].

5.3. Reduced Systemic Inflammation and Oxidative Stress Balance

Cancers develop as a result of two ongoing processes: inflammation and oxidative damage to cells. The ketone body BHB acts in two ways: it has direct anti‐inflammatory properties, and it acts as an NLRP3 inflammasome inhibitor, which prevents the release of IL‐1β and IL‐18, pro‐inflammatory cytokines [93]. It acts as a histone deacetylase HDAC inhibitor, which regulates the genes to reduce oxidative damage while enhancing the protective capabilities of the cells [92]. This protects the body from treatment‐induced damage while preserving its ability to fight infection. The KD diet reduces cancer‐related inflammatory markers, such as CRP, IL‐6, and TNF‐α, as indicated by preclinical and clinical trials showing enhanced body strength during cancer treatment [143]. The KD diet protects healthy cells from chemotherapy‐ and radiotherapy‐induced damage through two mechanisms, which also restore redox balance and induce cancer cell death by weakening mitochondria. The two functions of the KD diet indicate its ability to regulate both inflammatory and oxidative pathways, which are used together with other cancer treatment modalities [75, 151].

5.4. Accessibility and Cost‐Effectiveness as a Supportive Therapy

The second major advantage of KD as an adjunct therapy is that it provides easy access at low cost to patients. The drug development process has experienced delays because the product requires specialized manufacturing equipment, and medical facilities require expensive distribution methods that currently do not exist for KD treatment. The system helps people to control their health problems by changing their diets, and they can use things that are usually available at local stores for that. Diet‐based therapies are far cheaper than most cancer drugs, and at the same time, patients can continue their therapy with the help of dietitians and planned meal timings [4, 152]. By combining the classic KD and the MAD, which increases patient compliance while maintaining the treatment regimen and allowing personalization of the KD [17]. Public health organizations should adopt KD as a complementary treatment because it helps reduce hospital stays and their associated costs by treating complications that arise during medical procedures [153].

6. Limitations and Challenges

The primary obstacle to implementing KDs for cancer treatment exists because patients struggle to follow the diet and continue with their treatment. The KD differs from standard dietary plans because it requires patients to severely limit their carbohydrate intake to 20–50 g or less and to consume large amounts of fat, which can be challenging for patients experiencing chemotherapy‐ or radiotherapy‐related appetite loss, nausea, and changes in taste. Research shows that patient compliance tends to decline as treatment progresses, as patients with more‐advanced disease who experience fatigue and loss of appetite pose a greater challenge to adherence to their treatment regimen [4, 64]. The presence of taste disturbances, social eating habits, and cultural eating practices adds to the challenges faced by patients who would like to stick to their diet plans. The implementation of personalized nutritionist support, together with flexible dietary options, including modified Atkins and MCT‐based KDs, will enable patients to meet their dietary requirements while achieving therapeutic results from their diet plan [108]. The success of the KD in clinical oncology research faces major obstacles because most patients do not adhere to the treatment plan.

Another important limitation of using KD in cancer therapy is the potential for nutritional deficiencies and metabolic complications. When followed over extended periods, a high‐fat, very‐low‐carbohydrate diet may result in inadequate intake of essential vitamins, minerals, and dietary fiber if supplementation is not carefully planned and monitored [17]. Sustained adherence has also been linked with various metabolic disorders such as dyslipidemia, hyperuricemia, kidney stones, and fatty liver disease [20, 154]. Ketone acidosis is rarely seen, but it is still a possible risk in patients with poorly controlled diabetes, those who have impaired renal function, or are in severe catabolic states [155]. These factors underscore the importance of careful clinical monitoring, including frequent biochemical testing and a thorough nutritional evaluation. Although personalized KD regimens combined with proper supplementation, sufficient hydration, and regular reassessment can reduce the risk, safety issues remain a significant obstacle to the widespread use of KD in oncology.

The current clinical research environment for KD use as an adjunct cancer treatment is lacking in sufficiently large, well‐designed clinical trials. Most of the evidence today is derived from preclinical studies, small pilot studies, and individual patient case reports. The studies demonstrate beneficial effects; however, they are not statistically powerful enough to establish a causal relationship or to evaluate standardized treatment methods. Currently, there is a shortage of clinical trials that are adequately sized and properly designed for KD use as a cancer treatment support. Most of the evidence today is from preclinical studies, small pilot studies, and single‐patient case reports. Although the studies show a positive response to the treatment, they lack sufficient statistical power to establish causality or standardize treatment methods. Furthermore, the study results are less straightforward due to significant variation across studies, including different KD diet plans, patient groups, treatment methods, and assessment tools. The safety, efficacy, and long‐term effects of KD treatment in oncology are still a mystery due to the lack of sufficient RCTs with an adequate number of participants. The next multicenter RCTs are expected to deliver robust, evidence‐based data to justify the use of KD in cancer treatment [156]. The effectiveness of the KD is greatly influenced by the specific context, such as the type of cancer, the molecular characteristics, and the stage of the disease. According to the study, glioblastoma tumors, which rely on glycolysis and have mitochondrial dysfunction, are highly sensitive to the ketosis diet that leads to glucose shortage and metabolic stress [157]. Cancers that display a high degree of metabolic adaptability are capable of switching between fatty acid metabolism and ketone body metabolism, thus resulting in a reduced reaction or a complete loss of response to ketosis diets [27]. Advanced cancer patients undergo a two‐stage disease progression, which eventually leads to their body systems acquiring more metabolic flexibility and their body systems generating health problems that hinder the success of dietary treatments. The large differences in patient responses to KD treatments emphasize the importance of a precision medicine strategy. Considering tumor metabolic enzyme expression, mutation profiles, and metabolic imaging data may enable the identification of patients who would most benefit from KD. Conversely, applying KD without adequate patient stratification could undermine its great potential and is likely one of the reasons clinical studies sometimes yield inconclusive results.

7. Future Directions

Moving ahead, the inclusion of KD in cancer treatment poses several challenges, mainly because cancer treatment is slowly shifting towards highly personalized therapies. One of the most promising areas in this respect is precision nutrition, which means that the type of dietary therapy, for example, KD, is tailored according to the biological type of the patient's tumor. The development of metabolomics might enable the detection of tumors that are heavily dependent on glucose and have limited metabolic flexibility, thereby making them more susceptible to metabolic therapies such as KD [128]. Besides genetic changes, including mutations in IDH, PTEN, or mitochondrial genes, might also be helpful for patient selection and, consequently, for the adjustment of dietary strategies [158].

In addition to finding suitable patients, integrating KD with recent therapeutic methods might yield greater benefits. Combining KD with metabolic inhibitors targeting pathways such as glutaminase or mTOR, or with oncolytic viruses, would further exploit cancer cells' metabolic weaknesses and enhance treatment responses [159]. There is also a trend towards the use of ketogenic, mimetic, that is, ways of simulating ketosis by the use of exogenous ketone esters or small molecules that are able to reproduce the main metabolic and signaling effects of ketosis. Such means may be a more convenient and less burdensome option for patients than strict dietary regimens [160]. Besides this, KD combined with intermittent fasting or time‐restricted feeding has become popular because these methods can induce similar metabolic states, improve insulin sensitivity, and activate autophagy, which, in turn, may potentiate antitumor effects [161].

Moreover, future studies should take into account age and cancer type, as KD might not result in the destruction of all tumors. For instance, brain tumors seem to be very responsive to metabolic interventions since they have very limited metabolic adaptability, whereas blood cancers may need altered or totally different ways of treatment [162]. In the end, well, thought, out, large, large‐scale, randomized clinical trials that integrate these precision‐based strategies and contain metabolic and molecular analyses at a very detailed level will be indispensable to show the utility of KD and to justify its integration as a safe and effective intervention in oncology practice.

8. Conclusion

The KD is a metabolic therapy strategy that is being increasingly investigated for cancer treatment, with the main idea of helping established therapies such as chemotherapy and immunotherapy. Since many tumors share certain metabolic characteristics, such as dependence on glucose metabolism and mitochondrial dysfunction, the KD can make cancer cells more susceptible to treatments while normal cells are hardly affected. A considerable body of preclinical research demonstrates that the KD enhances the efficacy of chemotherapeutic drugs and immune checkpoint inhibitors. In addition, initial clinical cases suggest that, with careful patient selection, the KD is feasible, relatively safe, and may improve quality of life or stabilize disease. It is also important to note that ketone bodies not only serve as fuel molecules but also act as signaling molecules that modulate inflammation, oxidative stress, and immune responses, thereby providing an additional biological rationale for the KD in cancer therapy.

Even though it holds such potential, many hindrances that require solutions have been acknowledged to ensure KD's widespread acceptance in the medical field. It is hard for most patients to adhere to it for long, and the safety of this diet over the long term remains a matter of debate. Besides, we still do not have large, appropriately designed, randomized clinical trials that would be sufficiently conclusive to define the clinical benefit. Moreover, tumor responses differ greatly not only by cancer type but also by disease stage, which is why precision‐based strategies combining metabolic, genomic, and clinical factors should be used when patient selection is concerned. In the future, one way to increase the therapeutic effect of KD might be to use it in combination with metabolic inhibitors, oncolytic viruses, or time restricted feeding mechanisms. Besides, the creation of ketogenic, mimetic substances could be a great help in solving practical problems of diet adherence. Therefore, the KD should be considered a complementary, potentially valuable, and supportive measure rather than a substitute for standard cancer therapies. When it is clinically validated with due care, KD can be part of a highly personalized, metabolism‐focused approach to cancer treatment, resulting not only in better patient outcomes but also in enhanced quality of life.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File: mnfr70578‐sup‐0001‐SuppMatTables.docx.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.