Targeting tumor metabolism through precision nutrition: A therapeutic strategy to improve cancer outcomes

Abstract

Modern cancer therapies include chemotherapy, immunotherapy, radiation therapy, hormone therapy and newer methods like oncolytic viruses and chimeric antigen receptor T-cell therapy. These therapies are commonly used to manage cancer, but many patients face serious side effects such as cachexia and treatment related anorexia which can lead to a lower quality of life and a reduced ability to tolerate treatment. This review explores nutrition-based approaches that might help reduce these side effects and improve the effectiveness of these therapies. Dietary modulations like ketogenic diets, fasting mimicking diets and changes in macronutrient intake have shown promise in early studies and preclinical research. These approaches may interact with how tumors use energy and help patients better handle their treatment. However, the exact impact of these strategies on cancer therapy outcomes remains unclear and needs more research through well designed, large scale clinical trials. The review also examines dietary factors that could lower the risk of developing cancer, and it looks at how processed foods and alcohol increase cancer risk as well as how plant-based diets and certain micronutrients may help prevent cancer. These factors might reduce cancer risk by lowering oxidative stress, reducing chronic inflammation, altering gut bacteria and changing gene expression. Additionally, strategies tailored to specific stages of cancer treatment including assessing and optimizing nutritional needs pre-treatment providing supportive nutrition during treatment for conditions like mucositis and malnutrition and managing recovery has also been discussed. New experimental technologies such as nanoparticles like cargos, CRISPR-Cas9 and artificial intelligence as a key part of comprehensive cancer care are the key points which has been discussed with the goal of improving treatment results and enhancing the quality of life for cancer survivors.

Key Words: Cancer therapy; Dietary interventions; Fasting-mimicking protocols; Ketogenic diets; Macronutrient modulation; Precision nutrition

Core Tip: Precision nutrition is emerging as a complementary strategy to improve cancer outcomes by targeting tumor metabolism and reducing treatment-related toxicities. Dietary approaches, including ketogenic and fasting-mimicking diets, support therapy response, alleviate cachexia, and enhance quality of life. Personalized nutritional interventions may become integral to comprehensive cancer care.

INTRODUCTION

Cancer therapy landscape: Challenges and side-effects

Cancer continues to remain as one of the major health challenges globally, accounting for significant morbidity and mortality. According to the World Health Organization, cancer is responsible for approximately 10 million deaths every year, making it the second leading cause of death worldwide[1]. The increasing incidence is attributed not only to ageing populations, but also to lifestyle-related factors such as excessive tobacco use, poor dietary habits, lack of physical activity and environmental exposure[2]. Each year, millions of individuals are newly diagnosed. While early detection and improved awareness have enhanced prognosis in some cases, a large proportion of patients still present with advanced-stage disease, where therapeutic intervention becomes more complex and less effective.

Over the past few decades, cancer treatment has evolved significantly. The traditional triad of cancer therapy, surgery, radiotherapy, and chemotherapy- has been supplemented by more sophisticated approaches such as immunotherapy, targeted therapies, and precision medicine. Chemotherapy and radiotherapy aim to destroy rapidly dividing cells, yet they often lack selectivity, damaging healthy cells alongside malignant ones[3]. Immunotherapy, which harnesses the body’s immune system to recognize and eliminate cancer cells, has shown remarkable success in certain cancers like melanoma and non-small cell lung cancer[4]. Targeted therapies, which inhibit specific molecular pathways involved in tumor growth and progression (e.g., HER2 inhibitors in breast cancer, or tyrosine kinase inhibitors in chronic myeloid leukemia), offer greater specificity and reduced systemic toxicity[5]. Furthermore, advances in genomics and molecular diagnostics have enabled personalized medicine, allowing treatment regimens to be tailored to an individual’s genetic makeup and tumor profile - thereby improving efficacy while minimizing adverse effects[6].

Despite these encouraging developments, there are still many obstacles in the way of cancer treatment. Drug resistance, which can be acquired or intrinsic, is one of the main problems[7]. By changing drug targets, improving DNA repair systems, or up-regulating drug efflux pumps, tumors may evolve defenses against the cytotoxic effects of treatment[7]. Treatment is further complicated by tumor heterogeneity. These include both intra-tumoral (differences within a single tumor mass) and inter-tumoral (differences between tumors in different individuals or between multiple tumors within a single individual) heterogeneity. Consequently, a single therapeutic agent may not effectively target all cancer cell sub-populations[8]. Furthermore, systemic side effects and off-target toxicities remain common, especially with cytotoxic chemotherapeutic agents that are not precise enough to differentiate between healthy proliferating cells and malignant cells[3].

Particularly crippling and varied adverse effects of cancer treatment frequently results in a marked reduction in the quality of life for patients. Fatigue, nausea, vomiting, diarrhea, mucositis (inflammation of the mucous membranes) and alopecia (hair loss) are typical side effects[9]. Myelosuppression may result in more serious side effects such as anemia, an elevated risk of infection, and bleeding disorders[10]. Organ-specific toxicity such as cardiotoxicity (from anthracyclines), nephrotoxicity (from cisplastin), or neurotoxicity (from vincristine) can occasionally be brought on by therapy[11]. Aggressive treatments can worsen cachexia, a complex syndrome marked by weight loss and muscle atrophy that is frequently seen in advanced cancers[12]. These adverse effects compromise the effectiveness of treatment by limiting everyday functioning and possibly requiring dose reductions, treatment delays or discontinuation.

Therefore, despite significant advancements in oncotherapy, treatment limitations and unfavorable results continue to challenge clinical management of cancer. These issues highlight how urgently integrative approaches such as nutritional interventions, supportive care, individualized treatment planning and advancements in drug delivery systems are needed to improve treatment outcomes and overall well-being of cancer patients[13].

The imperative for nutritional interventions in oncology

The importance of nutrition in cancer treatment has received a lot of attention lately. Both cancer-related cachexia and malnutrition are common among cancer patients and are known to be independent predictors of poor treatment outcomes[14]. Traditional diet management is based largely on providing adequate energy and protein intake for individuals, to avoid weight loss; correcting nutrient deficiencies; and enhancing the quality of life during treatment. By comparison, precision nutrition incorporates individualized dietary recommendations based upon the unique characteristics of the patient such as; tumor biology, metabolism, type of treatment, genetics and molecular profile of the person, gut bacteria composition, nutritional status, and related biomarker analyses from each patient. Precision nutrition will not only work to optimize nutritional health but also look at how certain diet related changes may affect host metabolism, immune responses, treatment tolerance, and, where supported by evidence, tumor metabolic pathways. Furthermore, emerging evidence suggests that certain dietary patterns and nutrient composition can influence immune function, oxidative stress, inflammation and even the tumor microenvironment (TME)[15,16]. As a result, nutritional interventions are becoming more widely recognized as both supportive care and potentially integrative elements of therapeutic approaches that can increase effectiveness, reduce adverse effects and improve overall clinical results.

So, the purpose of this review is to examine the evolving role of nutritional interventions in cancer treatment. It discusses the biological mechanisms linking diet with treatment response and critically assesses the preclinical and clinical data pertaining to different dietary approaches including anti-inflammatory diets, fasting mimicking diets (FMDs) and ketogenic diets. This review also explores how customized nutrition may be used in conjunction with both established and new cancer treatments. An overview of the importance of nutrition during and after cancer therapy and the use of supportive nutrition in conjunction with emerging precision nutrition approaches as a supplement to established oncologic treatment modalities has been discussed. This review aims to demonstrate the critical role that strategic nutritional modulation can play in comprehensive cancer care by addressing the existing gaps in knowledge and practice. The literature included was identified through searches of major biomedical databases, including PubMed, Scopus, and Web of Science, using combinations of keywords such as cancer, nutrition, precision nutrition, ketogenic diet, fasting-mimicking diet, cachexia, immunotherapy, chemotherapy, radiotherapy, gut microbiota, and tumor metabolism. Priority was given to systematic reviews, meta-analyses, clinical guidelines, randomized clinical trials, and high-quality preclinical studies published in English. Additional relevant references were identified by screening the bibliographies of selected articles.

DIETARY RISK FACTORS IN CARCINOGENESIS

Diet, being the source of vital nutrients, plays a huge role in maintaining health and disease progression. The type and amount of nutrients a person consumes influences a multitude of health conditions like diabetes, hypertension, dyslipidemia, cancer[17]. All such diseases have both non-modifiable (e.g., age, sex, genetics) and modifiable risk factors. Among modifiable risk factors, diet is of utmost importance along with lifestyle choices, obesity and addiction[18].

In today’s world, there is an increase in intake of processed food; but this overconsumption of food mixed with preservatives, additives, artificial sweeteners expose us to multiple substances which may lead to metabolic dysregulation and promote tumor growth[19]. Intake of alcohol and exposure to known carcinogens lead to oxidative stress by either increasing production of free radicals or decreasing cellular anti-oxidant mechanisms[20]. Some types of cancer have been shown to be associated with specific types of food, which is depicted in Table 1, along with some protective dietary components.

Table 1 Dietary modulation of cancer metabolism: From nutritional risk factors to the ketogenic diet.

Cancer type	At-risk diet	Protective diet	Strength of evidence
Nasopharyngeal	Salt preserved food, nitrosamine	Fruit, vegetables, vitamin C, folate	Moderate
Oesophageal	Hot beverages above 65 °C	Fruit, vegetables	Strong
Stomach	Salt preserved food, nitrites, pickled vegetables	Fruit, vegetables, vitamin C, β-carotene, selenium, α-tocopherol, polyphenol	Moderate
Colorectal	Unprocessed red meat, processed red meat (nitrates, nitrites)	Milk, calcium, vitamin D, cereal fiber, wholegrain cereals, folate	Strong
Liver	Aflatoxin in grains, nuts, dried fruit stored in hot and humid conditions	Coffee	Strong
Pancreas	Processed red meat, saturated fats, sugary drinks	β-carotene, selenium, α-tocopherol, vitamin A, lycopene	Limited-moderate
Breast	Smoked meat, high fat diet	Isoflavones are largely from soya, vitamin D	Limited-moderate
Prostate	Dairy products, calcium	β-carotene, vitamin D, vitamin E, selenium, lycopene, isoflavone	Limited

The strength of evidence has been classified as strong-supported by consistent prospective cohort studies, convincing mechanistic evidence, and/or authoritative evaluations (WCRF AICR), moderate-supported mainly by prospective cohort studies with plausible biological mechanisms but lacking definitive randomized trial evidence: Residual confounding cannot be excluded and limited-evidence is inconsistent, derived largely from observational or mechanistic studies, or randomized trials have not confirmed benefit or harm. However, these results show only that the dietary component is associated with a change in cancer risk, not that the dietary component is responsible for, or causes, the change in risk. For example, study subjects with and without cancer may have other characteristics that differ than just their diet, and therefore, the observed difference in cancer may be due to these other factors or differences between the study subjects. Often, dietary patterns of participants living within the same geographic area share many lifestyle and environmental characteristics (e.g., obesity, smoking, alcohol consumption, level of physical activity, socioeconomic status, access to medical care, overall dietary quality) that can independently affect the development of cancer. Although prospective cohort studies often attempt to adjust for a variety of these variables using multivariable statistical methods, there will always be some degree of residual confounding and measurement error in the assessment of dietary consumption that cannot be completely eliminated. Thus, these findings should be interpreted with caution because association does not necessarily imply causation.

Neoplastic and immune cell metabolism is majorly regulated by the nutrients available in the TME[21]. Tumor cells undergo metabolic adaptations to establish an immunosuppressive metabolic microenvironment within the TME. By depriving vital metabolites such as glucose and oxygen and also increasing limiting mediators like lactate and adenosine, they impair the function of immune cells[22]. As a result, different subsets or clones of immune cells undergo these metabolic reprogramming including glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), the pentose phosphate pathway, fatty acid oxidation (FAO), fatty acid synthesis and the amino acid metabolic pathway[22].

From initiation, promotion, malignant transformation, invasion, and metastasis, chronic inflammation is widely recognized as an important contributor to carcinogenesis and is considered one of the enabling characteristics of cancer. Accumulating evidence suggests that inflammatory processes can influence each of these stages of tumor development; however, the relative contribution of inflammation varies considerably among different cancer types and individual patients[23]. Many tumors, including those without an obvious inflammatory etiology, exhibit an inflammatory TME; however, the composition and functional consequences of this inflammatory milieu are highly heterogeneous and depend on tissue type, genetic alterations, immune cell composition, and environmental exposures. The likelihood of cancer is greatly influenced by lifestyle and environmental factors that are closely linked to inflammation[24]. A significant amount of the worldwide cancer burden is caused by dietary practices, obesity, tobacco use, and chronic infections[25]. These influences can create a microenvironment that favors the development of a tissue that is conducive to ongoing inflammation in the form of tissue destruction and also the genomic instability or abnormal signaling of cells, leading to the continuing growth of tumors. In addition, some of these exposures may act together and interact with each other and with genetic vulnerability factors making it difficult to establish a direct cause and effect relationship for individual components.

Many observational studies have shown that consuming ultra-processed foods is linked to an increased risk of developing cancer, mainly due to their potential to cause obesity, but also because they lack essential nutrients and have some potentially harmful additives and contaminants from processing[26]. Chronic low-grade inflammation associated with obesity is one of several biological pathways through which obesity is believed to increase the risk of several cancers alongside different hormonal, metabolic, and immune system changes[27]. On alcohol intake, production of free radicals, increased cytosolic NADPH production, decreased reduced glutathione levels, etc. contribute to the development of a pro-inflammatory state[20]. Alcohol has been causally linked to several cancers, although its carcinogenic effects are believed to involve multiple interacting mechanisms, including oxidative stress, acetaldehyde-mediated DNA damage, and chronic inflammatory responses.

Cancer typically develops from a normal cell that has acquired one or more genetic mutations (known as ‘driver’ mutations) to allow it to proliferate and survive better than neighboring cells[28]. This process often involves several mutations accumulating in long-lived stem cells or progenitor cells[29]. Triggered by infections, irritants, allergies, or autoimmune illnesses, chronic inflammation which results from a milieu encouraging genetic damage and aberrant cell growth is believed to play a major role in carcinogenesis[30]. As illustrated in Figure 1, diverse external stressors converge on common inflammatory signaling pathways that drive chronic inflammation, genomic instability, immune dysregulation, and ultimately cancer initiation and progression.

Figure 1 Integrated mechanisms connecting external stressors, inflammation, and cancer progression. Figure was created using Canva (https://canva.link/Lu2v4qzacbsaruw). DAMP: Damage-associated molecular patterns; NF-κB: Nuclear factor kappa B; STAT3: Signal transducer and activator of transcription 3; H. pylori: Helicobacter pylori; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HPV: Human papillomavirus; EBV: Epstein-Barr virus; SLE: Systemic lupus erythematosus; JIA: Juvenile idiopathic arthritis; PM/DM: Polymyositis/dermatomyositis; ROS: Reactive oxygen species; AID: Activation-induced cytidine deaminase.

During inflammation, activated immune cells release reactive oxygen species (ROS) and reactive nitrogen intermediates, leading to DNA damage, genomic instability, angiogenesis and epigenetic modifications that elevate mutation rates[31]. Chronic inflammation can also facilitate the development of cancer due to the interference that ongoing inflammatory signals cause with mechanisms of DNA repair. Chronic inflammation can impair the body’s ability to repair mistakes made when copying DNA while also increasing the activity of an enzyme known as activation-induced cytidine deaminase (AID). Normally, AID helps diversify antibodies in B cells, but under chronic inflammation, it may become aberrantly expressed in epithelial cells. Experimental studies suggest that this inappropriate expression can contribute to mutations in oncogenes and tumor suppressor genes (TSGs); however, the importance of this mechanism appears to be tissue-specific thus leading to tumorigenesis[32].

CANCER PREVENTION THROUGH DIET

Dietary intake patterns cover a wide range of nutritional components and provide a comprehensive assessment of diets, which must take into account the complex interactions between foods and nutrients, as well as their wide-ranging effects on the physiology and composition of the human body.

Of the various dietary patterns, plant-predominant dietary patterns have consistently been associated with favorable health outcomes in observational studies, particularly those characterized by a high intake of fruits, vegetables, nuts, legumes, whole grains, and healthy oils, together with a lower intake of red and processed meats and ultra-processed foods[33]. However, much of the evidence linking these dietary patterns to reduced cancer risk originates from prospective cohort studies, and therefore demonstrates associations rather than definitive causal relationships. Plant-based diets include a variety of dietary patterns, even though they are frequently associated with vegan or vegetarian lifestyles. The phrase “plant-based” actually describes a diet that is mostly composed of foods derived from plants rather than being restrictive. This makes it possible to include small portions of meat, fish, dairy, and eggs. Therefore, a plant-based diet does not require the total and permanent elimination of animal foods, but it may replace animal products with plant alternatives[34].

According to the aforementioned broad definition, the traditional Mediterranean diet (MD) pattern has been regarded as a primarily plant-based diet, because it prioritises a low intake of dairy products, red meat, processed meats, and sweets; a moderate intake of fish and poultry, as well as wine with meals; and a high intake of olive oil, fruit, nuts, vegetables, cereals, herbs, and spices. Because MD uses fresh, seasonal, and minimally processed foods, it can also be regarded as a whole food diet[35].

The Nordic diet, the Dietary Approaches to Stop Hypertension (DASH), the Alternate Health Index-2010, and the vegetarian diet are among the other healthy dietary patterns that are often compared with the MD[36]. The two main features of each of these dietary types are that they are structured by including or excluding particular foods, and that they are based on particular guidelines[36].

One of the healthiest diets that has been studied the most is the Nordic diet, which includes foods like whole-grain cereals, fish, cabbage, rye bread, apples, pears, and root vegetables, since its inclusion of less beneficial options, such as sugar and margarine, is another characteristic, when evaluating its health impact, individual foods are considered rather than dietary habits as a whole[37,38]. The vegetarian diet can be analysed similarly; in this case, avoiding meat, fish, and poultry improves body mass index, which lowers the intake of saturated fatty acids and, consequently, the rates of obesity and overweight[39]. On the other hand, this dietary decision may lead to higher homocysteine levels and lower levels of sex hormones and vitamin B12[40]. In both cases, the improvement in disease prevention is linked to the diet’s capacity to reduce or prevent specific risk factors, like being overweight, obese, or experiencing hormonal changes[41]. These diets, however, do not have a complete protective and health-enhancing impact. Nevertheless, evidence regarding the magnitude of cancer risk reduction varies across cancer types and populations, and not all studies have reported consistent protective associations.

On the contrary, the MD offers numerous advantages associated with individual characteristics and external values pertaining to the preservation of traditions and customs, as well as environmental safe-guarding[42]. This dietary approach is noted for its numerous positive, healthful, and nutritional benefits, as evidenced by the extensive literature published from 1960 onwards regarding this dietary style[43]. In particular, the added value arises from a blend of healthy foods and their extensive nutritional advantages, including a high consumption of vitamins and nutrients, along with a variety of food options, ranging from vegetables and fruits to meats and fish, without prohibiting alcohol, adherence to the seasonal availability of each ingredient, the freshness of products in order to enhance the presence of protective nutrients and substances, and the incorporation of all accessible foods, including sweets, within a framework of careful moderation and frugality[44]. However, randomized controlled trials specifically evaluating cancer incidence as a primary outcome remain relatively limited, and therefore much of the evidence for cancer prevention relies on prospective cohort studies and secondary analyses rather than definitive clinical trials.

The abundance of antioxidants and anti-inflammatory nutrients such as high polyphenol concentration found in several MD foods, including legumes, fresh fruits, nuts, vegetables, fish, and particularly extra-virgin olive oil, has been proposed as one biological mechanism underlying the inverse association between the MD and cancer[45-47]. Experimental and mechanistic studies suggest that these bioactive compounds may help prevent cell deterioration, suppress cancer cell proliferation and impede metastasis[48].

Additionally, carotenoids and vitamins like C and E, flavonoids, and folates - nutrients known for their antioxidant qualities that help prevent DNA damage - are abundant in fruits and vegetables[49]. Omega-3 fatty acids, which are abundant in nuts like almonds, walnuts, and pumpkin seeds as well as fish, especially sardines and mackerel, which are staples of the MD, additionally help decelerate the progression of cancer by affecting angiogenesis, inflammation, metastasis, cell proliferation, and survival[50]. Moreover, cutting back on meat consumption can lessen the noxious effects of high-temperature cooking techniques and cut down on animal fat intake[51].

Together with an increase in antioxidant vitamins and phytochemicals, the fiber present in whole grains, vegetables, legumes, and fruits helps to lower insulin resistance, prevent the intestines from absorbing cholesterol, and decrease cholesterol synthesis in the liver[52]. Red wine consumption has produced conflicting results, but new research suggests that some of the micronutrients in wine, especially polyphenols like quercetin and resveratrol, may be protective against cancer[53]. When examining the holistic MD, which does not focus on individual foods but rather on the overall dietary pattern and its pathways leading to beneficial effects on various diseases including cancer, it has been found that this dietary approach yields several positive outcomes, like a reduction in lipid levels and modulation of their effects, promotion in anti-inflammatory, antioxidant, and anti-aggregating properties, modulation of cancer-related mediators such as hormones or growth factors, a decrease in the stimulation of hormones or other intracellular and extracellular signaling pathways involved in cancer, due to alterations in amino acid content, as well as modifications in gut microbiota resulting from enhanced and altered production of bacterial metabolites[54].

At present, MD is regarded as one of the most beneficial dietary patterns. Cross-sectional and prospective observational research conducted in Europe, the United States, and Australia has linked greater adherence to Mediterranean-style dietary patterns with a reduced prevalence and incidence of non-communicable diseases such as diabetes, cardiovascular disease, cancer, neurodegenerative disorders, and overall mortality[55-57]. The evidence supporting the relationship between the MD and cancer primarily stems from observational studies. A majority of these studies have identified a protective effect associated with high adherence to the MD against the onset of various types of neoplasms, indicating a general reduction in cancer risk ranging from 5% to 21%[33]. By types of cancer, risk reductions of 33% for gastric cancer[58], 36% for prostate cancer[59], 49% for hepatocellular cancer[60], 50% for colorectal carcinoma[61], 58% for head and neck cancer[62], 81% for lung cancer[63], and 6% in postmenopausal breast cancer[64] have been reported. A significant limitation of these studies is that dietary practices were recorded using quantified consumption frequency surveys or 24-hour recall methods, which are prone to bias and thus considered unreliable. The only clinical trial focused on cancer prevention is the PREDIMED study, which currently offers the highest quality evidence demonstrating the advantages of this dietary pattern on cancer incidence, reporting a 67% reduction in breast cancer risk among women at high cardiovascular risk who adhered to the MD supplemented with extra virgin olive oil[65,66]. Importantly, the evidence supporting dietary patterns such as the MD primarily relates to cancer prevention rather than cancer treatment. Although healthy dietary patterns are recommended to support overall health and nutritional status following a cancer diagnosis, current evidence does not establish that adherence to these diets alone improves therapeutic efficacy, reduces tumor progression, or enhances survival during active cancer treatment.

A growing body of research suggests that dysbiosis within the gut microbiota may play a crucial role in the advancement of cancer. This dysbiosis is increasingly recognized as an emerging hallmark associated with cancer biology, rather than a universally established defining characteristic of all cancers[67]. There is compelling evidence that Fusobacterium nucleatum and Bacteroides fragilis are significantly associated with the pathogenesis of colorectal cancer[68]. The immune system is impacted by the gut microbiota, which in turn affects how effectively cancer immunotherapy operates[69]. Since a 2015 article in Science found that the gut microbiota affects the modulation of the immunosuppressive response, there has been a lot of interest in the relationship between cancer immunotherapy and the gut microbiota[69]. However, much of the current evidence remains preclinical or is derived from observational clinical studies, and the precise microbial signatures that consistently predict treatment response have not yet been established.

Accordingly, modulation of the gut microbiota represents a promising therapeutic strategy, but its routine clinical application in oncology has not yet been established. Although gut microbiota modulation has the potential to improve treatment response, current evidence remains heterogeneous, and there is no consensus regarding the optimal therapeutic approach or patient selection criteria[70]. Even though there is hope that gut microbiota modulation could enhance the effectiveness of tumor treatment, there is still little consensus on how to regulate this process. Currently, intestinal microbiota transplantation[71], probiotics[72], dietary adjustments[73], and antibiotics[74] are utilized primarily for modifying the composition of the gut microbiota. Notably, nanomedicine is prepared in an interdisciplinary manner with the aim of targeting and eliminating specific pathogenic bacteria[75]. However, these technologies remain at an early stage of development, with limited clinical evidence supporting their use in cancer patients. The gut microbiota affects the effectiveness of medications in addition to the effectiveness of cancer immunotherapy. Interactions between medications and the resident gut microbiota can alter the microbiota’s abundance and composition, and the enzymes they produce can change the structures of the drugs, which can impact the drugs’ toxicity and biological activity[76,77].

By means of three distinct mechanisms, probiotics have been proposed to help prevent and potentially support the management of colorectal cancer. This includes resistance to colonisation by releasing antimicrobial peptides[78], lowering luminal pH[79] and/or directly interacting with pathogens (e.g., competing for nutrients and location, forming co-aggregates)[78], modulating immunity. Depending on the species and strains used, probiotics can have a variety of immunomodulatory effects to either reduce colonic inflammation by activating dendritic cells, decreasing T helper 17 (Th17) cells, increasing regulatory T cell (Treg) expression, and shifting macrophages to the M2 subtype, or increase antitumor immunity by increasing Th17 activity, decreasing Treg expression systemically, and reducing tumor cell expression of C-X-C chemokine receptor type 4 and major histocompatibility complex class I[80]. These findings underscore that probiotic effects are strain-specific and cannot be generalized across all probiotic formulations. Another proposed mechanism is an enhanced gut barrier function by promoting epithelial restitution via increasing the expression of tight junction proteins and mucin production. By upregulating or normalising expression of tight junction proteins like claudin-1, occludin, zonula occludens-1 (ZO-1), ZO-2[81], stimulating mucin production[82], lowering inflammation and aiding epithelial restitution[83], several probiotic strains like Lactobacillus rhamnosus, Lactobacillus plantarum and Escherichia coli Nissle 1917 have been shown to improve gut barrier integrity[76,81,82,84]. As illustrated in Figure 2, probiotics promote host health through three interconnected mechanisms: Colonization resistance, modulation of immune responses, and preservation of intestinal barrier integrity. However, clinical studies in oncology remain limited, and there is currently no consensus regarding the optimal probiotic strains, dosing regimens, treatment duration, or patient populations most likely to benefit. Consequently, routine probiotic supplementation cannot yet be recommended as a standard adjunctive therapy for cancer patients.

Figure 2 The three pillars of probiotic function: Colonisation resistance, immunomodulation, and barrier integrity. Figure was created using Canva (https://canva.link/taxbfp23h0tbful). DCs: Dendritic cells; Th17: T helper 17; Treg: Regulatory T cells; CXCR4: C-X-C chemokine receptor type 4; MHC-1: Major histocompatibility complex class I; ZO-1: Zonula occludens-1; ZO-2: Zonula occludens-2.

Probiotic foods and prebiotics, that promote a healthy gut microbiome, are abundant in the MD[85]. Fundamental elements of this diet include fermented foods like kefir, olives, and yoghurt, which supply the gut with probiotics. Additionally, the diet includes foods high in prebiotics, such as apples, asparagus, and artichokes, which support these good bacteria and create a balanced environment in the gut[86].

The promotion of some probiotic species like Bifidobacterium species in high-fiber and plant protein regimens were noted, whereas they were inhibited under high-lipid and red meat or animal fat input[78,80]. A significant mutualistic relationship between Bifidobacterium adolescentis and Eubacterium hallii was also observed under typical input of the MD with a starch-rich diet support[87]. It is known that Eubacterium hallii by itself is not able to utilize starch without assistance from Bifidobacterium adolescentis[88]. Another interesting mutualistic duo was found to be Bacteroides thetaiotaomicron and Methanobrevibacter smithii, with significant short-chain fatty acid (SCFA) production capacity that is promoted under MD input[89]. These findings are an indicator that certain health-promoting cliques in human gut microbiota might be evolved to co-utilize the nutritional composition provided specifically by the MD[90].

NUTRITIONAL MANAGEMENT ACROSS TREATMENT PHASES

Nutritional care in oncology is most effective when tailored to specific treatment phases, addressing the evolving needs of patients. Moving beyond a “one-size-fits-all” approach, precision nutrition improves treatment tolerance, manages therapy related side effects, enhances resilience and supports survivorship outcomes.

Pre-treatment: Laying the foundation

Optimizing nutritional status before treatment initiation is essential as malnutrition and micronutrient deficiencies affect up to 80% of patients with advanced cancer, compromising treatment tolerance, increasing hospitalization risk and reducing overall survival[91,92]. Proactive screening with validated tools, such as the Nutritional Risk Screening 2002 and Malnutrition Universal Screening Tool, along with personalized dietary counselling, is supported by current clinical guidelines and has demonstrated benefits in improving nutritional status, postoperative outcomes, and reducing treatment-related complications[85,86]. Fixing deficits in protein and micronutrients, including vitamin D, iron, antioxidants like vitamins C and E, and selenium, helps lower baseline oxidative stress and inflammation in the body[91]. It is especially important to get enough protein during this time to maintain lean body mass and support immune function[93].

Nutrition guided by biomarker data shows promise for pre-treatment optimization. High levels of inflammatory markers, such as interleukin-6 (IL-6) and C-reactive protein (CRP), have been proposed as potential indicators for omega-3 fatty acids because of their well-known anti-inflammatory effects[94]. Moreover, glucose and insulin levels have been explored as potential tools to individualize carbohydrate intake or ketogenic methods to reduce tumor growth caused by high insulin levels[95]. Profiling the microbiome may also help decide whether to include prebiotics and probiotics to boost gut health[96].

During treatment: Targeted dietary interventions

During chemotherapy: Chemotherapy frequently causes nutritional complications which includes nausea, anorexia, taste alterations and mucositis that leads to weight loss and treatment interruptions[97]. Evidence based interventions recommend small, frequent meals rich in energy, complex carbohydrates and moderate proteins to maintain nutritional status and body mass[91,97]. While soothing and cool foods such as smoothies may provide symptomatic relief, oral glutamine supplementation has shown potential benefit for chemotherapy-induced mucositis[98], but evidence across trials remains mixed and no consensus dosing has been established, and it is not uniformly endorsed by major guidelines such as European Society for Clinical Nutrition and Metabolism (ESPEN) and ASCO. Ginger and peppermint have demonstrated modest efficacy in reducing nausea in randomized control trials (RCTs)[99]. Additionally, omega-3-fatty acids may reduce systemic inflammation and preserve appetite and lean body mass[89,93]. Structured nutritional counseling further improves quality of life, reduces fatigue and enhances treatment adherence[85,91].

During immunotherapy: Immune checkpoint inhibitor (ICI) therapies require strong immune function, so it is essential to have enough protein intake of 1.0 g to 1.5 g per kilogram daily[100]. ESPEN and other expert groups recommend getting protein from high-quality sources[101]. Supplementing with branched-chain amino acids (BCAA) has been explored in preclinical and small clinical studies to help increase lymphocyte growth and cytokine production; however, this evidence remains limited, and BCAA supplementation is not currently endorsed in major clinical nutrition guidelines for cancer or immunotherapy[102]. Important micronutrients like vitamin C, zinc, and selenium have roles in modifying the immune response and supporting cellular immunity during immunotherapy[103]. New research shows that a high microbial diversity in the gut microflora links to better responses to immunotherapy[100]. This finding encourages studies on using prebiotic fibers, such as inulin, and fermented foods alongside standard treatment, although extensive clinical trials are still in progress[98,99]. Although these findings have generated considerable interest, interventions such as microbiome profiling, prebiotic supplementation, fermented foods, and probiotics remain investigational, with no standardized clinical protocols currently available.

During radiotherapy: Radiotherapy causes oxidative stress and localized inflammation, especially in gastrointestinal and oropharyngeal tissues. Protective dietary measures include antioxidants and foods rich in polyphenols, like curcumin, green tea catechins, and resveratrol. These have shown radioprotective effects by scavenging free radicals, primarily in preclinical studies, whereas clinical evidence remains limited and inconsistent. Importantly, use of antioxidants during radiotherapy is also controversial as some data suggests that intake of high doses of antioxidants can protect the tumor cells from the cytotoxic mechanism and thus hinder the efficacy of radiotherapy[104]. Consequently, routine supplementation cannot currently be recommended solely for radioprotection[105]. Carotenoids such as β-carotene and lycopene play a role in mucosal defense[106]. Supplementing diet with omega-3 fatty acids and probiotics has been effective in reducing the severity of radiation enteritis, particularly in patients with pelvic and abdominal cancers[94]. Well-established supportive care should include proper hydration and easy-to-digest, soothing foods like oatmeal, bananas, and yoghurt, as these helps promote mucosal healing[91]. Protein supplementation is especially important for older patients and those facing significant side effects from treatment[93].

Emerging therapies: Novel treatments like chimeric antigen receptor (CAR)-T cell and oncolytic virus (OV) therapies present unique nutritional challenges. After lymphodepleting chemotherapy before CAR-T cell infusion, the body requires protein-rich and immune-supportive diets to aid in immune recovery[107,108]. Researchers are looking into amino acids like arginine and glutamine for their roles in supporting T-cell metabolism and recovery[109]. OV therapies also rely on viral replication and the body’s antiviral response[110]. These therapies may need sufficient levels of micronutrients, especially vitamins A, D, and E along with zinc, to support immune function. There are currently no specific nutrition guidelines for CAR-T or OV therapies to support routine targeted supplementation. Therefore, nutrition strategies for CAR-T and OV therapies should be tailored to each patient and based on general oncology nutrition principles until more reliable data is available[111].

Post-treatment: Recovery and long-term survivorship

Recovery after active treatment centers on reversing cachexia, rebuilding lean muscle mass, and lowering the risk of recurrence[112]. Clinical studies strongly support high-protein diets that include omega-3 fatty acids to promote muscle growth and reduce systemic inflammation in selected patients[113]. Adding leucine and creatine helps muscular recovery in patients with cachexia but requires further confirmation in larger randomized clinical trials[114]. Additionally, foods rich in phytochemicals, such as cruciferous vegetables, berries, and whole grains, may contribute to favorable metabolic and inflammatory profiles, although their direct effects on cancer recurrence remain difficult to establish[115].

To ensure lasting health after cancer, it is best to follow plant-based eating patterns, especially the Mediterranean and DASH diets[116]. These diets emphasise fruits, vegetables, whole grains, nuts, and olive oil. They have been linked to significant decreases in cancer recurrence and cancer-specific death[47]. Meta-analyses show a 23%-34% reduction in overall mortality for survivors of breast, colorectal, and prostate cancer who follow these eating patterns[117]. Managing weight, limiting alcohol intake, and reducing processed and red meat are important steps that align with American Cancer Society guidelines[118]. Evidence from prospective cohort studies and meta-analyses suggests associations between adherence to these dietary patterns and improved survival among certain cancer survivors; however, these findings should not be interpreted as proof of causality because randomized intervention trials remain limited. Finally, adopting healthy lifestyle habits, like regular exercise, good sleep practices, and effective stress management, helps maintain metabolic health and lowers the risk of secondary cancers in survivors[119].

In summary, managing nutrition during treatment phases works best when it is specific to each phase, based on evidence, and focused on the patient. Established methods have shown benefits in improving tolerance, reducing toxicity, and aiding recovery. Ongoing clinical research, especially with new therapies, will clarify how precision nutrition fits into complete cancer care.

EVIDENCE-BASED DIETARY INTERVENTIONS

One of the main features of cancer is the altered cellular metabolic pathways that distinguish it from most normal tissue cells[120]. This important and remarkable metabolic alteration enables cancer cells to adapt to the metabolic needs necessary to sustain growth, multiplication, and survival under circumstances with fluctuating nutrient availability[121]. Oncogenic signaling pathways and the amplification or alternative splicing of metabolic enzymes are the main causes of this change[122]. Together with the known dysregulated glucose metabolism that leads to the production of extra amino acids and fatty acids, this alteration makes cancer cells dependent on a steady flow of nutrients and energy, which promotes the growth of tumor cells[122,123]. Increased absorption of glucose, which is essential for the synthesis of intermediates required for the synthesis of proteins, lipids, and nucleic acids, is a common characteristic of cancer cells. Furthermore, through increased glutamine uptake and glutaminolysis, which are redirected into biosynthetic reactions, cancer cells can sustain a consistent supply of intermediates in the TCA cycle[124]. The production of NADPH, which serves as a reducing agent for anabolic reactions and maintains cellular redox balance, must also increase in tandem with this increased biosynthetic activity[125]. Additionally, metabolites like acetyl-coenzyme A (acetyl-CoA) for acetylation, NAD+ for deacetylation, S-adenosylmethionine (SAM) for methylation, α-ketoglutarate for demethylation, and uridine diphosphate N-acetylglucosamine for glycosylation are responsible for the epigenetic changes that occur during cellular transformation and cancer progression[126]. Additionally, recent insights into the carcinogenesis process have indicated that cancer is a complex disease, and a simplistic examination of genetic mutations in cancerous cells is inadequate for a thorough understanding[127].

The metabolism of cancer cells is altered to enhance cellular growth, proliferation, and long-term sustainability, with notable increases in glucose uptake and the conversion of glucose to lactate, commonly referred to as the “Warburg effect”[124]. Evidence also suggests that the production of lactate via the Warburg effect grants cancer cells a selective advantage over normal cells in their microenvironment[124,128]. The exact connection between the Warburg effect and the development of cancer is still unclear, despite the fact that lactate is known to be an essential component of angiogenesis and is required for the growth and multiplication of cancer cells[129].

In the absence of oxygen, the non-oxidative pathway is crucial for ATP production in cancer cells through the conversion of glucose into lactate via fermentation[130]. Furthermore, cancer cells exhibit elevated levels of ROS due to the malfunctioning of the electron transport chain[131]. Given that glucose is a vital element for tumors, which rely entirely on it for their survival and growth, the ketogenic diet emerges as a dietary therapeutic approach that reduces body glucose levels while simultaneously increasing ketone body levels[95]. While many tumor types have been seen as unable to efficiently use ketone bodies because of reduced mitochondrial oxidative capacity, this is not the case for all. Several tumor types retain metabolic flexibility and can oxidize ketones under certain conditions. This means the anti-tumor effect of ketogenic diets cannot be explained only by cancer cells’ inability to use ketones. On the other hand, long-term ketogenic diet adherence and glucose restriction cause FAO in normal cells, which is necessary for the production of ketone bodies such as acetoacetate, β-hydroxybutyrate, and acetone[95]. These ketone bodies are essential for keeping healthy cells in a state of optimal condition because they are later transformed into acetyl-CoA and enter the TCA cycle to produce ATP[95,132].

Because of this, scientists have been concentrating more on finding or developing a diet-based approach as a new complementary therapy that affects the metabolic pathways of cancer cells in recent years. Numerous clinical and animal studies have shown the efficacy of these methods, which include intermittent fasting, prolonged fasting, the ketogenic diet, fasting-mimicking diet, and various forms of caloric restriction[133]. These studies also suggest that these methods may be used as preventive or adjunctive strategies in the treatment of cancer[133-136].

Ketogenic diet: Mechanisms and clinical efficacy

Extensive research indicates that ketogenic diet, or more generally, diets characterized by high fat, low carbohydrate, and sufficient protein content, may be effective for cancer treatment or prevention, either on their own or in combination with medications[137,138]. Numerous studies have examined the association between dietary choices and the reduction of chronic disease risks, such as cancer and age-related ailments, as well as the potential for extending lifespan[139]. The metabolic adaptations induced by ketogenic diets in normal vs cancer cells are summarized in Figure 3.

Figure 3 Differential metabolic pathways in normal vs cancer cells under a ketogenic diet. Figure was created using Canva (https://canva.link/k9yiddt9Ll5yksc). AMPK: AMP-activated protein kinase; CoA: Coenzyme A; TCA: Tricarboxylic acid; ATP: Adenosine triphosphate.

Dietary modifications target various pathways, including the insulin pathway, phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), mechanistic target of rapamycin (mTOR), ketone bodies, and the distribution of adiponectin and leptin proteins, along with insulin-like growth factor 1 (IGF-1)[139-141]. Both preclinical and clinical investigations have demonstrated the anti-aging and anticancer benefits of ketogenic diet[142]. Moreover, physical exercise, in addition to dietary management, has been shown to lower cancer risk across most types of cancer. Improper regulation of the PI3K/AKT pathway is closely associated with tumor development and increased resistance to cancer therapies, despite the fact that PI3K is activated after both the insulin receptor and IGF-1 receptor. mTOR, a protein kinase, is involved, and a number of circumstances and variables influence its signaling. It is stimulated by growth factors, mitogens, PI3K, AMP kinase, and hormones, including insulin[143]. Under low nutritional conditions, AMP-activated protein kinase (AMPK), PI3K, and mTOR are all acutely affected[139]. Ketogenic diet stimulates the AMPK signaling pathway, which has tumor suppressor functions, leading to the inhibition of mTOR signaling[142,143].

The potential of a high-fat diet to cause inflammation because of the elevated levels of lipids, particularly saturated fats, is one of its primary problems. Saturated fats have been shown to mimic the effects of lipopolysaccharide, which causes inflammation when it binds to its receptor on macrophages/monocytes and other innate immune cells[144]. Polyunsaturated fats, on the other hand, such as omega-3 fatty acids like eicosapentenoic acid and docosahexenoic acid, are known to have anti-inflammatory qualities[141]. An increase in the release of inflammatory cytokines into the local and systemic circulation is indicative of chronic inflammation[145]. Inflammation has recently been identified as a crucial aspect of cancer[146]. In various tissues and tumor types, a low-carbohydrate, high-fat diet emphasizing unsaturated fats has been shown to decrease the presence of tumor-infiltrating macrophages, lower levels of circulating and tissue cytokines, inhibit nuclear factor kappa B (NF-κB) signaling, and reduce cyclooxygenase-2 expression[139]. Therefore, the significant anti-inflammatory properties of the ketogenic diet contribute to its cancer-preventive effects[142]. The metabolic result of adhering to the ketogenic diet is the production of ketone bodies[141].

A significant concentration of β-hydroxybutyrate activates uncoupling protein-2 within mitochondria, thereby safeguarding cells against oxidative stress[106]. Conversely, its deficiency can lead to an excess of ROS, the secretion of pro-inflammatory cytokines, and the continuous activation of NF-κB[147]. Consequently, ketone bodies are essential in mitigating oxidative stress and prolonging the lifespan of patients[147]. Peptide hormones such as adiponectin and leptin are synthesized from visceral white adipose tissue. Adiponectin exhibits an inverse relationship with leptin and other adipokines. Reduced levels of adiponectin have been associated with type 2 diabetes, insulin resistance, metabolic syndrome, hypertension, cardiovascular diseases, and cancer. Multiple studies have demonstrated how the risk of cancer can be reduced and longevity increased by following ketogenic diet. Furthermore, decreased expression of pro-inflammatory cytokines is also a result of increased adiponectin levels, which activate a number of pathways such as AMPK, MAPK, and PI3K/AKT[148]. Ultimately, a direct link has been identified between a high-calorie diet and cancer risk, alongside strategies for cancer prevention through lifestyle changes such as increased physical activity, exercise, and adherence to healthy diets rich in fruits, vegetables, and whole grains, while being low in red meat and saturated fats[147].

Despite these mechanical and early clinical findings, ketogenic diets are not suitable for everyone. Caution is needed for cachectic patients, those with pancreatic insufficiency, severe malnutrition, glycogen storage disorders, FAO disorders, and other metabolic conditions. In these cases, additional stress on the body or lack of available nutrients may lead to worse health outcomes.

FMDs

FMDs represent specialized meal plans specifically designed to replicate the fasting state while simultaneously providing necessary calories and nutrients[149]. Their purpose is to alleviate the challenges associated with fasting while achieving effects akin to those produced by fasting. However, in contrast to fasting, FMDs also deliver essential micronutrients, including vitamins and minerals[149].

Although the exact mechanism is still unknown, weight management and a decreased risk of cancer have been associated with exercise and dietary calorie restriction. The primary driver of the Warburg effect, a characteristic metabolic profile of cancer cells is their metabolic reprogramming to favor aerobic glycolysis over OXPHOS, even when oxygen is plentiful[150]. Consequently, fasting may produce varying impacts on the sensitivity of chemotherapy in healthy cells compared to cancer cells, a phenomenon known as differential stress resistance[150,151]. The underlying principle of short-term fasting and FMDs is that these dietary strategies safeguard healthy cells from stressors, such as chemotherapy, while rendering cancer cells more susceptible to chemotherapy and other treatments[152]. Healthy cells can transition to a maintenance or repair mode when nutrients are limited or absent, as occurs during fasting, unlike cancer cells, where oncogenes inhibit the activation of such stress resistance[153].

Fasting leads to a reduction in plasma levels of IGF-1, insulin, and glucose, all of which are crucial for preventing apoptosis, fostering growth, and accelerating aging, ultimately contributing to cancer development[154]. However, these effects are only observed if fasting continues for a minimum duration of 48 hours[155]. A molecular rationale for this phenomenon is that insulin and IGF-1 mediate immunosuppression through the signal transducer and activator of transcription 3 (STAT-3)[156]. As fasting lowers, the levels of circulating insulin and IGFs, it could theoretically result in reduced immunosuppression and consequently enhance immune activation, which may have a beneficial antitumor effect. In addition to immunosuppression, the STAT3 and JAK-STAT3 pathways exhibit diverse effects, acting both as a strong tumor promoter and as a tumor suppressor factor linked to cell growth, apoptosis, angiogenesis, invasion, and metastasis[157].

Various plausible molecular pathways have been identified that fasting may influence, impacting cancer biology. The impact of calorie restriction on the toxicity of chemotherapy was examined in vitro in both normal and cancer cells[158]. In normal cells, serum starvation triggers AMPK activation, which stabilizes p53, leading to a halt in proliferation[158]. During this proliferation arrest, cells are relatively shielded from DNA damaging chemotherapy (such as CDDP)[159]. In cancer cells, serum starvation further activates the ATM/Chk2/p53 stress response signaling pathway[158]. This excessive activation of the ATM/Chk2/p53 pathway results in an overload of stress, which is believed to deplete the cellular stress response and make cancer cells more susceptible to DNA damaging chemotherapy[159].

According to in vivo studies, mice that were on calorie-restriction had lower activity in the PI3K-AKT and MAPK pathways[160]. These signaling pathways, MAPK and PI3K/AKT, are crucial for cell survival and proliferation and may contribute to cancer development, differentiation, proliferation, progression, and the upregulation of angiogenic cytokines[122,123]. The observed suppression of the RAS-MAPK and PI3K/AKT pathways suggests a potential connection between calorie restriction and cancer prevention[161]. These preclinical findings regarding molecular signaling imply that calorie restriction could enhance the therapeutic effects of DNA-damaging chemotherapy[161]. Clinical studies have indicated that the consumption of a FMD can trigger metabolic alterations and boost antitumor immunity in cancer patients[162]. Indeed, the outcomes of a clinical trial involving an FMD (NCT03340935) revealed that a severely calorie-restricted, five-day FMD regimen was well tolerated and led to significant systemic metabolic changes in patients with various tumor types who were simultaneously undergoing anti-tumor treatments[161,162]. Moreover, a five-day FMD regimen significantly modified intra-tumor immunity in breast cancer patients, as reported by another clinical trial known as DigesT (NCT03454282)[162]. Specifically, the FMD was observed to enhance the infiltration of cytotoxic and activated immune cell populations, including natural killer (NK) cells, M1-like macrophages, antigen-presenting dendritic cells, as well as total and activated intra-tumoral CD8+ T-cells. Immune signatures linked to improved clinical outcomes in cancer patients rose concurrently with these alterations[162]. Similarly, prolonged fasting or fasting-mimicking protocols may be unsafe in frail, sarcopenic, or significantly underweight patients, and should be undertaken only under close clinical and nutritional supervision.

Protein-restricted diet

The prevalent theory suggests that a high protein intake, especially among those under 65 years old, may raise the risk of overall mortality and cancer-related deaths[163]. To implement a protein-restricted diet, one can either reduce dietary protein intake or limit the number of amino acids consumed[164]. Recent studies have shown that limiting dietary protein is associated with a lower incidence of tumor development and a reduced risk of death[165]. The restriction of dietary protein and specific amino acids, such as serine, methionine, and BCAAs like leucine, isoleucine, and valine, has been proven to hinder tumor growth[166].

The IGF-1 signaling pathway is one way that protein restriction may inhibit the growth of tumors. It has been observed that mice fed a low-protein diet (4% kcal protein) exhibit lower IGF-1 levels and slower tumor progression than mice fed a high-protein diet (18% kcal protein) in mouse models of breast cancer or melanoma[163]. A low-protein diet has been correlated with decreased IGF-1 levels in patients aged 50 years to 65 years, which in turn lowers their cancer mortality risk[163]. On the other hand, a low-protein diet has been associated with a higher mortality rate in older patients (aged 65 and above), indicating that a life-stage-specific strategy for protein intake may enhance health span and longevity[163]. Additional potential mechanisms for cancer prevention that may be influenced by protein restriction could include mTOR signaling, amino acid metabolic programming, fibroblast growth factor 21, and autophagy[165]. Protein restriction carries risks, especially for older or frail patients. Possible negative effects include faster muscle loss, weakened immune function, slower healing of wounds and tissues, and a worsening of cancer-related weight loss. The use of protein restriction depends largely on the patient’s age, nutritional status, type of cancer, and stage of treatment. It should be approached carefully and only in patients who are properly chosen for it.

In addition to the overall effects mentioned, specific dietary limitations on certain amino acids, like serine and glycine, have been linked with extended survival in mouse models of different tumor types[167]. The mechanisms accounting for this survival advantage may involve the rectification of abnormal cellular nucleotide, protein, and lipid synthesis; enhancement of mitochondrial function; and alterations in epigenetic modifications[168]. The antitumoral impact of a low-protein diet also relies on fostering immunosurveillance against cancer, whereas the dietary restriction of amino acids might negatively influence the metabolic reprogramming of the TME in several ways[163]. In various mouse models, a reduction in dietary methionine has been shown to suppress tumor growth and enhance anti-tumor immunity by increasing both the quantity and cytotoxicity of tumor-infiltrating CD8+ T-cells[169]. Furthermore, studies reveal that lowering dietary protein or methionine/cysteine can alter the way tumor-associated macrophages infiltrate and combat tumors. As a result, myeloid-derived suppressor cells (MDSCs) decrease and tumor-infiltrating CD8+ T-cells significantly increase. Mechanistically speaking, a low-protein diet has been shown to prevent the mTOR pathway from being activated and promote the growth of an antitumor phenotype in macrophages by boosting the quantity of M1-polarized macrophages[170].

Combining a diet low in protein with a vaccine or anti-programmed cell death protein 1 (anti-PD-1) treatment has demonstrated a marked reduction in tumor growth and an increase in survival rates[171]. Importantly, the implementation of a methionine-restricted diet led to a significant rise in the population of tumor-infiltrating CD8+ T-cells and cytotoxic granzyme B+CD8+ T-cells, an effect that was amplified when used in conjunction with immunotherapy; additionally, dietary methionine restriction has been shown to suppress tumor growth and can enhance tumor control when combined with PD-1 blockade, according to another study; mechanistically, this dietary strategy resulted in a decrease in metabolites such as SAM, which regulates the methylation processes of N⁶-methyladenosine (m6A) in cancer cells; in addition to reducing the levels of PD-L1 and V-domain Ig suppressor of T-cell activation in cancer cells, the decreased SAM levels also altered the m6A modification rate[169].

Limiting methionine and cysteine have also been connected to alterations in gut microbiota, which probably impacts immune system dynamics- leading to a significant decrease in the relative abundance of several members of the Ruminococcaceae and Prevotellaceae families, while increasing the presence of some members of the Lactobacillaceae family[170].

High-salt diet

High-salt diet (HSD) has long been regarded as a risk factor and a trigger for malignancies. However, recent research has shed new light on the impact of sodium intake. As studies progress, it is becoming increasingly evident that salt can accumulate in the interstitium, influencing immune cell differentiation, activation, and function due to the effects of extracellular hyper salinity[172]. Furthermore, the consumption of a high-sodium diet can result in increased tissue sodium levels, affecting immune responses within microenvironments and ultimately influencing the development of immune-regulated diseases such as infections and cancer[173].

HSD, which consists of 4% sodium chloride (NaCl), is acknowledged as a potent immunomodulator capable of provoking a significant inflammatory response[174]. Research indicates that elevated salt levels can enhance antitumor immunity by altering the roles of MDSCs, which helps inhibit tumor growth[175]. A recent study found that HSD lowered the cytokine production necessary for MDSC expansion, leading to a reduction in the number of MDSCs in the TME[176]. Consequently, the two main types of MDSCs developed distinct phenotypes. M-MDSCs differentiated into antitumor macrophages, while PMN-MDSCs adopted a proinflammatory phenotype, leading to the reactivation of T-cell antitumor functions[176]. Additionally, high salt levels have been shown to induce the conversion of anti-inflammatory Tregs into proinflammatory Th1 cells, resulting in the secretion of the inflammatory cytokine interferon (IFN)-γ[177].

In another study, salt acted as an adjuvant that improved the efficacy of anti-PD-1 immunotherapy in tumor regression[175]. In particular, HSD promotes NK cell-mediated tumor immunity by inhibiting PD-1 expression while elevating levels of IFN-γ and the serum concentration of hippurate; it is important to note that hippurate is a product of microbial benzoate metabolism recognized as a metabolic indicator of successful PD-1 immunotherapy in patients who respond[174]. Although the primary anti-tumor effect of HSD lies in the modulation of immune cell function, additional mechanisms beyond immunomodulation have also been identified in a mouse model of breast cancer[156]. HSD showed a reduction in lung metastasis and tumor growth, perhaps by simulating calorie restriction or causing hyperosmotic stress[178].

Nevertheless, excessive salt consumption may result in a pro-inflammatory state, which could have a detrimental effect on cancer outcomes, even though it may help increase the effectiveness of cancer treatments[179]. Consuming large amounts of salt is known to increase the risk of developing lung, testicular, bladder, renal, pancreatic, oesophageal, and gastric cancers, among other cancers in humans[173]. It has been demonstrated that HSD causes chronic inflammation, which may in turn cause DNA damage, cancer transformation, or persistent cell proliferation[178]. However, the presence of a conclusive link is still unclear[179].

A crucial part of the HSD action mechanism is IL-17, particularly IL-17A[180]. Th17 cells, which are a primary source of IL-17A, have been found to develop in reaction to a HSD. Excessive production of IL-17A has been linked to various diseases and can lead to inflammation and different immune responses. Moreover, in the context of breast cancer, an HSD has been shown to facilitate tumor progression and lung metastasis, increase the number of Th17 cells, and activate the MAPK/ERK signaling pathway in breast cancer cells via the secretion of IL-17F[180]. The rise in IL-17F secretion leads to the uncontrolled expression of protumor genes and induced inflammatory responses, which ultimately speed up the proliferation, migration, and invasion of breast tumors[181]. Additionally, the combination of elevated NaCl levels with sub-effective IL-17 has been shown to lower levels of ROS and reactive nitrogen intermediates, and promote the growth of breast cancer cells[182]. Additionally, recent research has shown that a HSD can disrupt the growth and operation of NK cells in mice[183]. Therefore, it can be concluded that dietary salt may have two effects on tumorigenesis. The contradictory findings may be due to the fact that different tissues and stages of tumor development are affected differently by high salt concentrations.

Although the burden of gastric cancer attributable to high salt intake declined between 1990 and 2021 in China, Japan, and South Korea, high salt consumption remains an important contributor to gastric cancer-related mortality and disability-adjusted life years, particularly among older adults and men. However, these findings should be interpreted cautiously because they are based on modeled population-level estimates and observational data, which cannot establish causality[184].

BIOLOGICAL MECHANISMS LINKING DIET AND THERAPY

The efficacy of systemic cancer treatments like chemotherapy, radiotherapy and immunotherapy can be significantly modulated by the host’s nutritional status and the direct biological effects of dietary components. The following mechanisms summarize the principal pathways through which nutrition may modulate therapeutic response, with emphasis on concepts not discussed in previous sections.

Metabolic reprogramming of TMEs

Cancer cells exhibit distinctive metabolic changes, a hallmark of cancer that enables rapid proliferation and survival in a resource-limited TME[185]. Dieting and fasting can target the following vulnerabilities to enhance treatment sensitivities.

The Warburg effect and glucose competition: Cancer cells often rely on aerobic glycolysis (the Warburg effect) for energy and building blocks as already discussed before[186]. Dietary strategies, such as time-restricted eating or specific carbohydrate modification, may reduce the circulating levels of glucose, insulin and IGF-1[187]. By reducing these growth signals and competing for glucose, dietary changes can potentially ‘starve’ cancer cells, besides sensitizing tumor cells to conventional therapies like chemotherapy or radiation, which are often more effective under conditions of metabolic stress[153].

Modulation of inflammation: The high rate of glycolysis in the TME leads to a build-up of lactic acid and an acidic pH, which drives immune suppression and drug resistance[188]. Certain dietary patterns, like those high in fruits and vegetables with an alkalizing effect, can help reduce chronic and systemic inflammation, as measured by CRP, creating a less hospitable environment for tumor growth and metastasis[189].

Gut microbiome crosstalk with treatment response

The trillions of microorganisms in the gut, collectively the gut microbiome, are profoundly affected by diet, and, in turn, exert control over the host immune system, influencing the effectiveness and toxicity of cancer treatments[190].

Immunotherapy efficacy: The microbiome has emerged as a major predictor of response to ICIs[190]. A diverse, healthy, and fiber-rich MD promotes the growth of beneficial bacteria like Akkermansia muciniphila or certain Bacteroides species, whose metabolites, such as SCFAs like butyrate, prime immune cells. This immune-priming is crucial for mounting an effective anti-tumor T-cell response, enhancing ICI efficacy[143].

Chemotherapy toxicity: The microbiome also affects the metabolism of chemotherapy drugs, a process called ‘microbial-drug crosstalk’; an imbalance in the microbiome, called ‘dysbiosis’, can lead to the inactivation, or, conversely, the toxic activation of drugs, contributing to severe side effects like neutropenic fever and life-threatening diarrhea[191]. Prebiotics and probiotics can be used to mitigate this damage and restore gut barrier integrity[192].

Epigenetic modulation via bioactive compounds

Epigenetics involves reversible changes to gene expression, like DNA methylation and histone modification, without altering the DNA sequence. Bioactive compounds found in food can directly manipulate these processes, offering a non-toxic way to influence tumor biology[193].

Reactivation of TSGs: Many aggressive cancers silence crucial TSGs through aberrant DNA hypermethylation. Dietary phytochemicals can act as natural epigenetic modulators. Sulforaphane from cruciferous vegetables like broccoli sprouts, and Epigallocatechin Gallate from green tea have been shown to inhibit histone deacetylases and DNA methyltransferases. This inhibition can lead to the re-expression of silenced TSGs like p16 (CDKN2A), p21 (CDKN1A), BRCA1, and PTEN, potentially inhibiting cancer cell growth, and making them more susceptible to standard therapies[193].

Inflammation and redox balance: Bioactive compounds like curcumin from turmeric, and resveratrol from grapes can epigenetically regulate the expression of genes involved in the inflammation pathway and oxidative stress, thereby reducing the systemic environment that fuels cancer progression[194].

NOVEL APPROACHES AND FUTURE PERSPECTIVES

Future nutritional oncology will rely on highly targeted, biologically active interventions guided by novel technologies.

Nutraceutical innovations

Nutraceutical food or food components that provide health benefits beyond basic nutrition - are being optimized to overcome challenges like poor absorption and lack of specific targeting.

Nanoparticle-mediated delivery of phytochemicals

Many phytochemicals like curcumin and resveratrol possess potent anti-inflammatory and epigenetic-modulating effects, but their clinical use is severely limited by poor bioavailability[145,146]. Encapsulation in nanoparticles (NPs) like liposomes, polymeric micelles, or solid lipid NPs protect these compounds from degradation in the gut and liver[195]. NP delivery drastically increases systemic bioavailability and promotes selective accumulation within the TME via passive or active targeting, enhancing the drug’s synergy with traditional chemotherapy while reducing systemic toxicity[196].

Probiotic/prebiotic engineering for microbiome therapy

Manipulating the gut microbiome to enhance anti-cancer immunity and reduce toxicity is a rapidly evolving field, moving beyond simple over-the-counter supplements. Using synthetic biology approaches, researchers are genetically modifying commensal bacteria like probiotics to engineered probiotics (“smart bacteria”) to act as live microbial delivery vehicles[197]. These “smart bacteria” can be designed to sense the TME by the low oxygen and locally produce and secrete therapeutic payloads like anti-tumor proteins, immune-stimulating cytokines, or enzymes that convert a harmless prodrug into an active chemotherapy agent[198], or target solid tumors directly, enhancing local drug concentration[197]. Custom-designed prebiotics, called ‘precision prebiotics’ are now being developed to selectively feed and enrich specific beneficial bacteria like Akkermansia muciniphila (SCFA producers) that have been correlated with positive responses to immunotherapy[199].

Advanced technologies

The next generation of personalized nutrition requires tools that can simultaneously analyze the patient’s entire biological system.

CRISPR-Cas9 for personalized metabolic targeting: The CRISPR-Cas9 gene-editing system is emerging as a critical tool for identifying individual metabolic vulnerabilities in a patient’s tumor[200]. Researchers use CRISPR-Cas9 to systematically knock out genes involved in cancer metabolism (e.g., genes for glucose uptake or glutamine processing) in tumor cells derived from a specific patient[201].

Personalized target identification: Identification of gene deletion that impair cancer cell viability reveals the tumor’s metabolic Achilles’ heel, facilitating the development of targeted therapies that selectively disrupt essential metabolic pathways while minimizing toxicity to healthy tissues[202].

Artificial intelligence-driven diet optimization using multi-omics data: Artificial intelligence (AI)-driven personalized nutritional oncology integrates multi-omics data including genomics, transcriptomics, metabolomics and microbiomics to generate comprehensive patient profile[203]. Machine learning models analyze this complex, high-dimensional multi-omics data and identifies subtle, interconnected patterns, for example, “Patients with mutation X, high blood metabolite Y, and low bacteria Z will respond best to a low-fat, high-fiber diet”[204]. The final output is an AI-driven, optimized diet plan designed not just for symptom management, but to directly alter the patient’s internal metabolic environment to maximize the efficacy of their specific anti-cancer drug regimen. This represents the ultimate goal of nutritional ‘precision medicine’[205].

Regulatory, ethical, and implementation considerations: These technologies remain confined to preclinical research or early exploration studies and have not yet been incorporated into standard oncology practice. Their movement toward clinical application is constrained by several factors, including the need to satisfy rigorous safety and efficacy requirements for engineered probiotics and NP-based systems, unresolved ethical questions surrounding CRISPR-based strategies and equitable access to AI-driven personalized nutrition, substantial financial demands for development and implementation, and the lack of supporting infrastructure such as multi-omics data workflows and trained personnel in most clinical settings, particularly in resource-limited regions.

CLINICAL TRANSLATION AND CHALLENGES

Addressing dietary adherence and socioeconomic barriers

Even though the importance of nutrition in enhancing clinical results during cancer treatment is becoming more widely acknowledged, it is still very difficult to ensure that patients follow their diet consistently. This problem is caused by a wide range of interrelated factors which frequently result in inadequate nutritional intake that may jeopardize the effectiveness of treatment and patient recovery[206].

Treatment related side-effects including nausea, vomiting, diarrhea, xerostomia (dry mouth), mucositis and changed taste and smell are one of the main challenges[207]. A patient’s appetite and capacity to eat or tolerate particular foods may be significantly diminished by these side effects making it challenging to meet their nutritional needs[189]. Additionally, the motivation or energy to prepare or consume balanced meals may be further diminished by general malaise and fatigue during chemotherapy or radiation therapy[207].

Cultural dietary restrictions and preferences are also highly crucial. When standardized dietary recommendations clash with their customary eating habits or religious dietary practices, patients may find it difficult to adjust[208]. Patients are less likely to follow diet plans that are not flexible or culturally-sensitive, which could further comprise their nutritional status[209]. A comprehensive, multi-faceted strategy in needed to overcome these obstacles. Culturally-appropriate dietary interventions that satisfy clinical nutritional objectives while honoring patient’s food preferences and regional eating customs is one possible solution[210].

Food insecurity, which is especially common among marginalized groups and in low- and middle-income nations, exacerbates these problems[192]. Patients who are struggling financially might not have the money to buy nutrient dense, high-quality foods, or use specialized medical nutrition products. Following recommended dietary regimens can be practically impossible due to limited availability of some foods, inadequate transportation infrastructure, and reliance on government rations and food aid[211].

Furthermore, in many rural places, access to qualified nutrition professionals is restricted[193]. Patients frequently lack proper support due to time constraints during clinical visits and lack of individualized counselling, even in cases where dietary guidance is available[212]. For people with complex nutritional needs brought on by co-morbidities or advanced disease stages, this gap is particularly important.

Educational initiatives that educate patients and caregivers on the role nutrition plays in cancer treatment, useful meal preparation techniques, and diet-based side effect management[213]. Patient-supportive environments can be created through community-based programs like cooking classes, support groups, and collaborations with nearby non-governmental organizations[214]. Institutional and governmental support, such as insurance coverage for oncology nutrition, subsidies for therapeutic foods, and the incorporation of dietitians into oncology teams is an urgent need of the hour[211]. Where in-person services are lacking, innovative delivery models like remote counseling platforms, mobile health applications (apps), and tele-nutrition services can fill the void[213].

Successful examples of multidisciplinary integration include institutional prehabilitation programs that incorporate oncology dietitians into surgical and medical oncology teams, as well as community-based nutrition initiatives in low- & middle-income countries that use task-shifted counseling delivered by trained community health workers and emphasize locally available, culturally appropriate foods. Reimbursement policies differ widely across health systems, and in many settings nutritional counseling and medical nutrition therapy are not separately covered, which can limit the routine inclusion of dietitians in oncology care teams. Improving dietary adherence during cancer treatment therefore requires more than clinical nutrition expertise alone; it also depends on socioeconomic sensitivity, policy support, and active community engagement at the grassroots level. Only through this broader, coordinated approach can nutritional therapy become a practical and effective component of comprehensive cancer care for patients across all socioeconomic backgrounds.

Standardizing guidelines for cancer therapy phase nutrition

Cancer patients’ nutritional requirements are highly dynamic, and change during the pre-treatment, active therapy, recovery, and survivorship stages of the disease. Dietary intake, nutrient metabolism, and general nutritional status are all impacted by the distinct physiological difficulties, metabolic demands, and psychological stressors that each step brings[211]. Pre-treatment nutrition aims to increase treatment tolerance by maximizing nutritional reserves and addressing pre-existing deficiencies[189]. Managing side effects like altered taste, anorexia, nausea, vomiting, mucositis, and diarrhea can hinder food intake and nutrient absorption, and it becomes more important during active chemotherapy and radiation[207]. Restoring energy, repairing damaged tissue and gaining back lost muscle mass become the main objectives during the recovery phase[215]. In contrast, the survivorship phase places a strong emphasis on the long-term dietary strategies to manage comorbidities, prevent recurrence and enhance the quality of life[216].

Standardized, evidence-based dietary recommendations for every stage of cancer care are conspicuously lacking, despite these phase specific requirements[217]. Due to variations in practitioner expertise, institutional protocols and resource availability, current clinical practices are highly diverse[195]. Due to this heterogeneity, nutritional interventions are frequently inconsistent which can result in either undernutrition which is linked to poor wound healing, decreased therapy tolerance and impaired immunity, or, overnutrition, which may raise the risk of metabolic problems and recurrence[218].

Harmonized guidelines that precisely define nutrient requirements viz., calories, proteins, and micronutrients intervention timing viz., early vs reactive nutrition and procedures for continuous nutritional monitoring and reassessment throughout treatment are urgently needed to close this critical gap[219]. These recommendations are based on solid clinical data, and developed by a multidisciplinary team that includes researchers, dieticians, clinical nutritionists and oncologists. Crucially, they also need to be flexible enough to accommodate the healthcare, socioeconomic and cultural realities of various patient groups[209].

Research gaps: From preclinical models to human trials

Even though there is mounting evidence that nutrition plays a part in cancer prevention and treatment, preclinical research and sparse observational data still dominate the current research landscape. Numerous nutritional interventions have shown encouraging anti-tumorigenic or, treatment enhancing effects in cell culture systems and animal models. These range from specific micronutrients like vitamin D, omega-3 fatty acids, and selenium, to more general dietary patterns like the MDs or ketogenic diets[217]; however, it is still very difficult to apply these findings to practical oncology practices.

The physiological and metabolic differences between human and animal modes of nutrition represent one significant drawback. The digestive enzyme activity, gut microbiome composition, immunological response, and nutrient metabolism of rats which are frequently employed in cancer research differs a lot[220]. The translational fidelity of preclinical results to human outcomes is called into question by these discrepancies.

Moreover, the human studies that are currently available are frequently of a small-scale, retrospective, or heterogeneous in design, which means that confounding factors like cancer type, stage, treatment plan, and comorbidities are not controlled[91]. Since many are cross-sectional or observational, it is impossible to prove a link between dietary interventions and clinical outcomes, like quality of life, survival rates, side effect management, or treatment responses[217].

Hence, there is an urgent need for strong, forward-looking, multicenter RCTs that use nutritional protocols which are standard and can be repeated, constant dietary monitoring of people, group participants by the type, stage and treatment of their cancer, and include both short term (inflammation, side effects, body composition) and long-term end points (recurrence, survival, patient reported outcome)[221]. These kinds of trials should also consider how people’s nutritional needs change based on their genetics, gut microbiota, treatment method, and metabolic status, as this aligns with the principles of precision nutrition.

A major challenge in nutritional intervention trials is assessing dietary adherence accurately. Self-reports and food frequency questionnaires can be influenced by memory and social pressure. Therefore, objective intake biomarkers, including metabolomic adherence markers, are needed to improve measurement accuracy. Dietary confounding also poses a significant issue. Factors such as baseline diet quality, supplement use, physical activity, and socioeconomic status can affect outcomes in cancer patients. Future studies should include standardized collection of these factors and, when possible, controlled feeding protocols to better address these variables.

To enhance reproducibility and clinical relevance, biomarkers of nutritional status and treatment response should be consistent across studies. Combining omics approaches like metabolomics and nutrigenomics with real-world data from digital tracking platforms or electronic health records may improve translational value. Tackling these challenges will be crucial for advancing nutritional science in oncology and for providing the evidence needed to shape clinical guidelines, public policy, and the incorporation of dietary strategies into standard cancer care.

CONCLUSION

Precision nutrition is rapidly evolving from a supportive adjunct into an integral therapeutic strategy in oncology, capable of modulating treatment response, mitigating side effects, and enhancing quality of life. Dietary interventions, caloric restriction, and macronutrient tailoring have demonstrated metabolic reprogramming effects that can improve the efficacy and tolerance of conventional cancer therapies, including but not limited to, interventions such as caloric restriction, fasting, and ketogenic diet in precision nutrition[222]. For instance, fasting-mimicking diets have been developed that impede tumor progression and reshape gut microbiota toward stimulating improved antitumor immune responses and synergizing with immunotherapy in preclinical models[223].

This review emphasizes a call to action for an integrated framework in precision nutrition in oncology, including pre-treatment biomarker-guided assessment through metabolic and inflammatory profiles, therapy-specific dietary strategies, and after-treatment rehabilitation plans[224]. By establishing such a framework, it will permit personalized dietary prescriptions according to the tumor metabolic phenotypes, gut microbiome composition, stages of treatment, and patient physiology in order to enable dynamic adjustment of nutrition to maximize benefit and minimize harm.

The dual role of diet in cancer prevention and progression also places added demands on structured nutritional guidance across the continuum of care. Pro-inflammatory and highly processed diets enhance cancer risk through mechanisms involving oxidative stress and dysregulated metabolic signaling, while plant-rich, microbiota-supportive diets promote protective epigenetic and immune effects[225]. These insights, when translated into oncology practice, would include nutrition as one of the modifiable components in both cancer prevention and adjunctive cancer therapy.

Policy implications from these advances are significant. Public health and institutional policies are urgently needed to formally incorporate precision nutrition into the standard of oncology care, including reimbursement for nutritional assessment and counseling, standard certification for specialists in oncology nutrition, funding robust clinical trials, and integration of dietary interventions into clinical practice guidelines to assure equitable patient access[91].

Future directions in this regard will include the use of multi-omics datasets like genomics, metabolomics and microbiomics to further refine nutritional interventions at a level of individual specificity; development of AI-based dietary decision support tools; and clinical testing of state-of-the-art breakthroughs in NP-enhanced nutraceutical delivery, and CRISPR-guided metabolic modulation. These technologies hold great promises to go beyond a promising concept to transform precision nutrition into a clinically validated therapeutic modality that will improve outcomes and enhance survivorship in cancer care.