REVIEWS

Developing dietary interventions

as therapy for cancer
Samuel R. Taylor   1,2,3, John N. Falcone1, Lewis C. Cantley   2
and Marcus D. Goncalves   1,2 ✉
Abstract | Cancer cells acquire distinct metabolic preferences based on their tissue of origin,
genetic alterations and degree of interaction with systemic hormones and metabolites.
These adaptations support the increased nutrient demand required for increased growth and
proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack
robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled
diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific
enrolment criteria that inappropriately grouped together subjects with disparate tumour and
host metabolic profiles. This imprecision may have masked the efficacy of the intervention for
appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that
occur across multiple types of cancer. We describe how these vulnerabilities could potentially be
targeted using dietary therapies including energy or macronutrient restriction and intermittent
fasting regimens. We also discuss recent trials that highlight how dietary strategies may be
combined with pharmacological therapies to treat some cancers, potentially ushering a path
towards precision nutrition for cancer.

1
Division of Endocrinology,
Department of Medicine,
Weill Cornell Medicine,
New York, NY, USA.
2
Meyer Cancer Center, Weill
Cornell Medicine, New York,
NY, USA.
3
Weill Cornell/Rockefeller/
Sloan Kettering Tri-​I MD–PhD
program, New York, NY, USA.
✉e-​mail: mdg9010@
med.cornell.edu
https://doi.org/10.1038/
s41568-022-00485-​y
Diet plays a role in virtually all aspects of cancer includ-
ing tumour initiation, progression and response to treat-
ment. For example, estimates suggest that up to one-​third
of the most common cancers are preventable, in part,
through dietary modification1–3. These associations were
established using large-​scale population-​based observa-
tional cohort studies, which provide valuable information
about correlations but cannot assess causation and suf-
fer from the notorious difficulty of accurately recording
dietary intake4,5. Controlled, mechanistic studies in pre-
clinical models have greatly improved our understanding
of how tissues utilize nutrients and the impact diet may
play in tumour initiation, progression and treatment
response. These studies have shown that diet can supply
the tumour with nutrients such as sugars and lipids that
can be used for tumour growth6; modulate systemic hor-
mones such as leptin, insulin, insulin-​like growth factor 1
(IGF1) and oestradiol that promote tumour cell pro-
liferation and survival7,8; and support the development
of obesity, which creates a milieu that favours tumour
initiation and progression8. As the links between dietary
factors and tumour initiation have been well reviewed
and summarized elsewhere9–11, our focus in this Review
is the impact of diet on tumour progression and how this
information is being translated into anticancer therapy.
We are on the precipice of a revolution in the way we
treat patients with cancer. Several rigorous preclinical
studies in mice, such as those by Hopkins et al., Caffa et al.
and Maddocks et al., have shown that dietary interven-
tions enhance anticancer therapy and improve cancer
outcomes12–14. The translation of these findings is well
underway with early-​phase clinical data supporting their
feasibility and safety15,16. Over the next 5 years, random­
ized controlled trials will be conducted to establish the
importance of diet on clinical outcomes in patients with
cancer. In this Review, we describe the key genetic and
metabolic features of tumours and their host tissues that
should make them vulnerable to dietary interventions.
We assess the state of the field and offer suggestions on
how to make precision nutrition a reality for cancer
treatment.
Metabolic vulnerabilities of cancer
General pathways of nutrient metabolism
The reprogramming of cell metabolism is a hallmark of
cancer17. Transformed cells adapt to a state of unregu-
lated cell growth and proliferation by upregulating nutri-
ent uptake and anabolic processes (Fig. 1). Sugars, amino
acids and fats are the basic dietary nutrients that support
the growth of cancer cells.
Glucose, the most extensively studied nutrient in
cancer biology, is a primary energy source for cells and
is obtained from the digestion of dietary carbohydrates
or generated de novo by anabolic processes in the liver

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Electromotive force
The electric potential
generated by the position
of charged molecules, such
as when partitioned across
a membrane.
ATP synthase
A mitochondrial enzyme
that phosphorylates
ADP to make ATP.
GLUT5
or kidney. Once imported via glucose transporters,
glucose can be metabolized in cells in two main ways. The
first and ancestrally older path is glycolysis. Glycolysis
takes place in the cytosol and breaks down glucose to yield
ATP, reducing equivalents, such as NADH, and pyruvate.
The second, oxidative phosphorylation, uses energy
from the oxidation of reducing equivalents to create an
electromotive force across the mitochondrial inner mem-
brane, reducing and consuming oxygen in the process.
This potential difference dissipates through ATP synthase
to generate ATP. Oxidative phosphorylation is a more
Fructose Glucose
GLUT1–GLUT4
efficient way to generate ATP per unit of glucose as com-
pared with glycolysis, but less efficient than glycolysis
when considered per unit of oxygen18.
The vast majority of ATP comes from the coupling of
glycolysis with oxidative phosphorylation but this link is
perturbed in two scenarios. The first is hypoxia, where
oxygen becomes limiting and the final electron transfer
of oxidative phosphorylation is halted. Hypoxic cells
upregulate glycolysis to generate ATP and reduce the
overflow of NADH18. The second scenario occurs in cer-
tain rapidly proliferating cells such as T cells, embryonic
Lipoproteins
LDLR

• ROS mitigation
KHK • Nucleotide synthesis
SDH HK
F1P Glycogen G6P PPP Cholesterol
SLC1A4 Glycine G6PD
Lipid droplet
ALDO Fatty acid
Glycine reservoir
and serine Lipid membrane
DHAP Glycerol-3-P triacylglycerides
Glyceraldehyde Glyceraldehyde-3-P Oleate
SCD
Serine
PHGDH O2
3-Phosphoglycerate FAO Stearate Fatty
Amino acids acids
and nucleotides αKG Glutamate CPT1 CD36
ATP ATP Palmitate
PEP
FASN
PKM2
LDH
Lactate Lactate Pyruvate Malonyl-CoA
PDH ACC
MCTs Aspartate
ACLY
Acetyl-CoA Acetyl-CoA Acetate
Proteins and Oxaloacetate
nucleotides ACSS1 ACSS2
Citrate Citrate MCTs
Steroid hormone
CO2 IDH2 IDH1 synthesis
αKG
ATP
O2 Epigenetic dysregulation
mtIDH1/2
αKG (D)-2HG
ROS
BCATs
Propionyl-CoA
GSH Glutamate
Proteins and LATs
GSS
Cysteine nucleotides
Glycine GLS

Glutamine Arginine

BCAAs,
SLC7A11 SLC1A5 ATs methionine
Cystine Glutamate Glutamine Arginine and threonine

Fig. 1 | nutrient utilization in cancer. Various pathways mediate
conversion of extracellular sugars, fats and amino acids into energy or
building blocks for anabolic processes. Enzymes critical to and/or frequently
upregulated in cancer in these pathways are shown, colour coded
according to their primary nutrient association: fructose (beige), glucose
(pink), lipid uptake and degradation (yellow) and amino acid metabolism
(blue). ACC, acetyl-​CoA carboxylase; ACLY, ATP citrate lyase; ACSS,
acetyl-CoA synthetase; ALDO, aldolase; ATs, arginine transporters;
BCAAs, branched-chain amino acids; BCATs, branched-chain amino
acid transaminases; CPT1, carnitine palmitoyl transferase I; FAO, fatty acid
oxidation; FASN, fatty acid synthase; G6PD, glucose-6-phosphate
dehydrogenase; GLS, glutaminase; GLUT, glucose transporter; GSS,
glutathione synthetase; (mt)IDH, (mutated) isocitrate dehydrogenase; KHK,
ketohexokinase; LATs, L-type amino acid transporters; LDH, lactate
dehydrogenase; LDLR, low-density lipoprotein receptor; MCTs,
mono-carboxylase transporters; PDH, pyruvate dehydrogenase; PHGDH,
phosphoglycerate dehydrogenase; PKM2, pyruvate kinase isoform M2; PPP,
pentose-phosphate pathway; SCD, stearoyl-CoA desaturase; SDH, sorbitol
dehydrogenase; SLC1A4, solute carrier family 1 member 4; SLC1A5, solute
carrier family 1 member 5; SLC7A11, solute carrier family 7 member 11.

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Ketone bodies
Metabolites such as
β-​hydroxybutyrate and
acetoacetate, which are
produced during hepatic
fatty acid oxidation and
can be used as energy
substrates by some tissues.
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Brain
Limited serine, glycine
High uptake of glucose,
lactate, glutamine
Breast
Local fat reservoir
3
High uptake of fatty acids,
lipoproteins, methionine
Sensitive to insulin/IGF1, 5 Intestine
steroid hormones
Liver
Exposed to intestinal/pancreatic
metabolites via portal circulation
High uptake of lactate, organic
acids, bile salts, short-chain
fatty acids
Sensitive to insulin/IGF1,
steroid hormones
Uterus/endometrium
Sensitive to insulin/IGF1,
steroid hormones
Local tissue environment/function factors Nutrient uptake preference
Fig. 2 | Tissue-specific metabolism. Notable metabolic features of various tissues. Anatomic location of these tissues
as well as metabolic demands of their normal function may impart vulnerabilities that can be targeted with diet and/or
pharmacotherapy. See main text for relevant references. BCAAs, branched-​chain amino acids; IGF1, insulin-​like
growth factor 1.
stem cells and tumour cells19–21. Here, regardless of oxy-
gen levels, cells typically exhibit high rates of glycolysis
and lactic fermentation. Lactate was long thought to be a
mere waste product of glycolysis, but is now recognized
as an important fuel source for human tumours and
healthy tissues22–24. In fact, stable isotope tracing studies
in fasted mice reveal that lactate incorporation into
tricarboxylic acid (TCA) cycle intermediates surpasses
that of glucose in all tissues except the brain24,25.
In addition to glucose and lactate, fructose also plays
an important role in the metabolism of many different
tissues. Although the small intestine and liver see the
largest concentrations of dietary fructose, serum fruc-
tose rises significantly after fructose consumption and is
metabolized by tissues such as the kidney, prostate and
bone marrow26–29. Inside the cell, fructose can be cleaved
into glycolytic intermediates and oxidized for energy
production. Despite using many similar pathways to
glucose, fructose metabolism is uniquely regulated
and often results in different downstream end points30.
Studies in mice suggest that fructose can reprogramme
metabolic pathways for anabolic metabolism and cell
survival31, a role that may be particularly important in
solid tumours32–34.
Other nutrients such as amino acids serve as build-
ing blocks for anabolic processes. Glutamine is a
non-essential amino acid arising from dietary sources,
muscle degradation or de novo synthesis pathways. Via its
conversion to α-​ketoglutarate, glutamine provides carbon
for TCA cycle intermediates that can then be siphoned
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Lung
Variable O2 exposure
1
High uptake of lactate, fatty acids
Pancreas
2 High synthetic burden
High uptake of amino acids
(glutamine, alanine, BCAAs)
4
6
• Steep O2 gradients
• Direct exposure to dietary
7 nutrients and microbiota-
8 derived metabolites
High uptake of sugars, glutamine,
short-chain fatty acids
Prostate
Local source of fructose and citric
acid in seminal fluid
High uptake of fatty acids,
citrate, lactate
Sensitive to steroid hormones
Hormone sensitivity
off for various anabolic processes such as the synthesis of
fatty acids35. In contrast to glutamine, the branched-​chain
amino acids (BCAAs) (leucine, isoleucine and valine) are
essential amino acids primarily obtained from dietary
sources. Studies in mice show that these can be taken
up by many tissues and tumours to be incorporated into
newly synthesized proteins or oxidized for fuel36,37.
Fatty acids are a dense source of energy that can be
obtained from the diet and stored in the body as triglyce­
rides. In times of low food intake, mammals catabolize
triglycerides and release the resulting fatty acids and
glycerol. Glycerol can be used by cells as a glycolytic,
gluconeogenic or lipogenic substrate. Fatty acids can
be oxidized to generate ATP, reused in the synthesis of
other lipid moieties such as phospholipids and choles-
terol esters or stored in intracellular lipid droplets. When
oxidized by the liver, fatty acids generate ketone bodies,
which are released into circulation and fed into the TCA
cycle in certain tissues25. These processes are frequently
upregulated in rapidly proliferating tissues such as
tumours38–40.
Tissue-​specific metabolism
Cancer cells acquire distinct metabolic preferences based
on their tissue of origin, genetic alterations and degree
of interaction with systemic hormones and metabolites.
The tissue of origin has a particularly strong effect on
metabolite abundance and metabolic gene expression in
tumours owing to engrained, lineage-​dependent prefer-
ences for sugars, fats and amino acids41–44 (Fig. 2). For the
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Triple-​negative breast
tumours
Breast tumours with low levels
of oestrogen receptor (ER),
progesterone receptor and
HER2 overexpression and/or
amplification. Typically,
these tumours carry a worse
prognosis than other types.
sake of brevity, this Review focuses on the metabolism
of a subset of tissues that have a high predilection for
malignant transformation as well as strong literature
supporting a relationship with dietary nutrients. For the
interested reader, excellent reviews are available summa-
rizing what is known about how diet and tumour metab-
olism relate in other cancer types, for example gastric
and kidney cancers45,46.
Brain. The brain is a unique organ that depends on the
uptake and oxidation of glucose and/or ketone bodies
and is also separated from systemic circulation by the
selectively permeable blood–brain barrier. High glu-
cose utilization is driven, in part, by expression of the
gene encoding the transporter solute carrier family 2
member 3 (SLC2A3), which has a high affinity and
trans­port capacity for glucose47. Interestingly, mouse
studies reveal that there is marked heterogeneity in
glucose uptake within different regions of the brain48.
Furthermore, a large body of evidence including tracer
imaging studies in mice and humans indicates that neu-
rons may prefer to use lactate generated by local astro-
cytes as a primary fuel49. Mouse and rat studies suggest
that the brain is also capable of metabolizing ketone
bodies during fasting, although the uptake and usage is
also spatially heterogeneous50–52. Fatty acids, meanwhile,
are seldom used by neuronal cells to meet energetic
demands25,53. Similarly, amino acids such as glutamine
are rarely oxidized by brain cells25. Glutamate is an exci­
tatory neurotransmitter than can cause neurotoxicity if
it accumulates, so it is rapidly converted to glutamine
by astrocytes and then transported back to neurons49.
Primary brain tumours adapt metabolically to grow
and survive. For example, many brain tumours express
higher levels or different isoforms of glycolytic enzymes
(for example, hexokinase, pyruvate kinase, pyruvate
dehydrogenase (PDH)), which provide them with specific
advantages in the brain’s unique environment (reviewed
in detail elsewhere49). Some of these unique features
may be exploited for therapy or diagnosis. For example,
in vitro studies indicate that depriving brain tumours of
glucose may be a useful therapeutic strategy as normal
neurons, but not glioma cells, are capable of surviving
on ketone bodies54. A subset of particularly aggressive
brain tumours promote glycolysis by downregulating
the mitochondrial pyruvate transporter subunit MPC1,
which makes cells dependent upon glutamine uptake
in vitro49,55,56. Mutations in isocitrate dehydrogenase
(IDH1 or IDH2) occur in 70% of intermediate-​grade glio-
mas and affect glioma sensitivity to nutrient deprivation57;
in  vitro tracing studies suggest that these tumours
particularly depend on glutamine58–60 (Fig. 1).
Nutrient availability also appears to affect the growth
of metastatic tumours within the brain. For example, the
brain has relatively low availability of serine and fatty acids
relative to serum, and mouse models indicate that breast
cancer metastases to the brain have increased reliance on
de novo generation of these components61,62. Furthermore,
nuclear magnetic resonance (NMR) labelling studies of
resected human tumours reveal that metastases from a wide
variety of primary sites can acquire the ability to oxidize
acetate as a fuel source when they arrive in the brain63.
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Breast. Mammary glands within breast tissue have a
high capacity to synthesize large amounts of macro­
molecules, which get exported into milk. The substrates
for this process are diet-​derived and include glucose,
fatty acids, lipoproteins and amino acids (especially
methionine)64. Much nutrient uptake by the breast is
regulated by insulin, IGF1 and steroid hormones such as
oestrogens and progesterone. For example, fluorodeoxy-
glucose (FDG) uptake in human breast tissue increases
with progesterone levels, and uptake and production of
lipids and proteins are strongly regulated by insulin65–68.
Dysregulation of the pathways involved in hormone
sensing and nutrient uptake in the breast can promote
cancer development. For example, the PI3K pathway is
typically hyperactivated in human breast tumours via
mutations in the gene for the main catalytic subunit,
PIK3CA (ref.69). PI3K is a lipid kinase that responds
to environmental growth signals such as insulin and
IGF1 to promote proliferation and nutrient uptake70.
Studies with patient-​derived cell lines show that hyper-
activation of PI3K is one way that oestrogen receptor
(ER)-​positive tumours may evade hormonal therapy71.
Correspondingly, data from mouse models and humans
treated with PI3K inhibitors show that tumours upregu-
late ER signalling as an escape strategy72. These findings
have prompted clinicians to begin targeting both PI3K
and ER — an approach that is proving effective in some
patients with breast cancer73.
The molecular features of breast tumours impact
nutrient uptake and metabolism. Human imaging studies
corroborate preclinical models showing that ER-​positive
tumours are relatively oxidative and consume lactate
and citrate, whereas triple-​negative breast tumours are
more glycolytic lactate exporters74. The expression of
oestrogen-related receptors (ERRs), orphan nuclear
receptors with structural similarity to ER, can also change
breast tumour metabolism. For example, human
genomic studies and in vitro models indicate that ERRα
activity promotes the expression of myriad metabolic
enzymes and confers an aggressive glycolytic phenotype
with a worse prognosis75. Human genomic studies and
xenograft mouse models also show that triple-​negative
breast tumours depend on de novo synthesis of serine,
which is limiting in the tumour microenvironment and
can be further depleted via diet76–78.
Fatty acid metabolism also appears important for
the development of certain molecular subtypes of breast
cancer. For example, compared against breast tissue
from healthy women, normal tissue from women who
later developed cancer showed upregulated fatty acid
uptake and transport, lipolysis, lipid peroxidation and
epithelium–adipose tissue crosstalk79. Uptake of exog-
enous fatty acids portends a worse prognosis and is
typical of aggressive, triple-​negative tumours80. Fatty
acid metabolism may also be perturbed in local adipose
deposits in the breast. In vitro co-​culture studies show
that adipocytes can deliver fatty acids to tumour cells and
induce gene expression changes that enhance tumour
cell migration81,82. Adipocytes also generate oestrogen via
aromatase, which may explain why oestrogen levels are
much higher in benign human breast tissue and tumours
than in serum83.
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Proliferative phase of the
endometrial cycle
The phase of the endometrial
cycle in which the
endometrial cells rapidly
proliferate in preparation
for possible implantation
of a fertilized embryo.
NATuRE REVIEwS | Cancer
Endometrium. Similar to the breast, the endometrium
is a hormone-​responsive tissue with high fluctuations
in metabolic demand. Studies from mouse and human
endometrial stromal cells show that glucose trans-
porter expression and glucose uptake are positively
regulated by progesterone and negatively regulated by
oestrogen84. Moreover, insulin stimulates the growth of
the endometrial mucosa, especially in the proliferative
phase of the endometrial cycle where IGF1 signalling is
essential85. In mouse models, cell-​autonomous activa-
tion of the PI3K pathway is sufficient for the initiation
of endometrial tumours86, and the PI3K pathway is fre-
quently activated in human endometrial carcinoma6,87.
More than 90% of human endometrial tumours have
genetic alterations in the PI3K signalling pathway, often
by activating mutations in PIK3CA, or loss-​of-​function
mutations in PTEN, the gene encoding a phosphatase
that directly opposes PI3K (refs6,87). These alterations
likely underlie the clinical associations of endometrial
cancer with biomarkers of hyperinsulinemia such as
fasting glucose, insulin, c-​peptide (insulin production),
haemoglobin A1C (chronic hyperglycaemia) and dietary
glycaemic load6.
Prostate. As with the breast and endometrium, the
prostate is highly sensitive to sex hormones. In partic­
ular, testosterone drives glucose uptake, which can be
detected via FDG-​PET and reversed with oestrogen
administration in rats88. In vitro and mouse models also
show that testosterone significantly accelerates incorpo-
ration of amino acids into protein and of acetate into
fatty acids and citric acid89. These changes help support
the primary biosynthetic role of the prostate to produce
seminal fluid, which is rich in citric acid and hydrolytic
enzymes arising from specialized epithelial cells. These
cells are highly glycolytic and have diminished capacity
for oxidative phosphorylation to enable them to gene­
rate and export citrate90. Seminal fluid is also rich in
fructose, and studies from human tissue suggest that
this fructose is generated de novo from glucose via the
polyol pathway91. This pathway uses aldose reductase to
reduce glucose to sorbitol, and then sorbitol dehydro-
genase (SDH) that oxidizes sorbitol to fructose (Fig. 1).
Interestingly, SDH is an androgen-​regulated gene that
is expressed in benign and malignant human prostate
cancers, in addition to the seminal vesicles92.
As with most other tumour types, cancerous trans-
formation increases nutrient uptake and utilization
in prostate cancer. Interestingly, mouse and human
tissue studies show that prostate cancer cells regain the
ability to perform oxidative phosphorylation during
transformation90. This adaptation allows these tumours
to readily consume and oxidize locally produced nutri-
ents such as citrate and lactate74,90. Moreover, emerging
evidence suggests that fructose can be a key substrate
for prostate cancer cells. For example, human primary
prostate tumours have high expression of SLC2A5,
the main fructose transporter28. Fructose may arise
from dietary sources or the tumours may gain access
to fructose-​dense fluid during seminal vesicle inva-
sion, which confers a worse prognosis in humans even
above other local invasion93,94. Fatty acids may also be
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important for prostate cancers, as suppressing their
uptake slows tumour progression in mouse models95,96.
Lung. Stable isotope labelling studies in healthy pigs
show that lung metabolism is notable for relatively
high consumption of hydroxybutyrate and acetoacetate
(ketone bodies), glutamine and saturated fatty acids97.
Nutrient uptake in the lung is not particularly sensitive
to systemic hormones. For example, there are minimal
changes in the contribution of glucose and lactate to
TCA cycle intermediates with fasting and refeeding, as
compared with other tissues25.
The lung is an excellent example of a tissue where
local effects likely alter tumour metabolic phenotypes.
As in many other tumours, mutations in primary lung
tumours occur in pathways that are associated with
increased glucose uptake and flux to anabolic pathways.
These mutations include genes in the epidermal growth
factor receptor (EGFR)–PI3K pathway, oncogenes such
as KRAS and MYC, and tumour suppressor genes such as
STK11 (ref.98). However, lung tumours with these altera­
tions often have different metabolic phenotypes com-
pared with genetically similar tumours in other tissues.
This distinction may be due to the unique features of
the lung environment, which offer a set of metabolic
advantages to primary and metastatic tumours alike.
For example, studies in mouse models show that the
lung environment may better allow pyruvate and proline
metabolism and, thereby, preferentially support breast
cancer metastasis99,100. Another example comes from
in-​human stable-​isotope tracing studies that found that
non-​small-​cell lung cancer (NSCLC) tumours maintain
high levels of glucose oxidation and can use a wide variety
of TCA substrates including, possibly, lactate101. In this
study, tumour metabolism was highly heterogeneous
between and within tumours, suggesting that variations
in the tumour environment within the same tissue also
alter metabolism101. A final illustration of the tumour
site altering the metabolic phenotype comes from mouse
studies that show that KRAS-​mutant pancreatic tumours
avidly scavenge their microenvironment for nutrients via
macropinocytosis, but KRAS-​mutant NSCLC tumours
take up comparatively less — even when derived within
the same organism37,102.
Some metabolic features of lung tumours may prove
to be metabolic vulnerabilities. For example, human
lung tumours express high levels of fructolytic enzymes
relative to normal lung tissue, and inhibiting fructose
uptake reduces tumour growth in xenograft models34.
Glutamine dependence has also been reported in some
preclinical KRAS-​driven tumour studies, with cells
carrying KRAS-​G12V being less dependent on glu-
tamine than cells expressing KRAS-​G12(C/D) (ref.103).
However, other studies in mouse models suggest that
glutamine metabolism is dispensable for fuelling the
TCA cycle when glucose is present104,105. KRAS-​mutated
tumours may also be sensitive to therapies targeting
BCAA and fatty acid metabolism. BCAA uptake is
elevated in NSCLC tumours versus normal lung, con-
sistent with low serum levels early in clinical disease,
and deletion of the BCAA transporter impairs tumour
formation in mice 37,106. Fatty acid metabolism may
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Anapleurosis
Typically referring to the
‘refilling’ or ‘fuelling’ of
the tricarboxylic acid (TCA)
cycle with amino acids to
drive biosynthetic reactions.
also be a promising target, and at least one enzyme,
acyl-coenzyme A synthetase long-​chain family member 3
(ACSL3), is highly expressed in human NSCLC and is
essential for KRAS-​mutant lung cancer tumorigenesis
in mice107.
Pancreas. The primary role of the pancreas is anabolic:
to synthesize and secrete hormones and enzymes. This
process requires a large influx of amino acids, which
serve as both building blocks for protein synthesis and
fuel for TCA cycle-​dependent amino acid production.
Out of 11 organs thoroughly profiled in mice and pigs,
the pancreas shows the greatest use of amino acids25,97.
These amino acids are consumed and repurposed by
zymogen-​producing acinar cells25,36.
Despite its role as a major endocrine organ and expo-
sure to high levels of insulin, the uptake of nutrients by
the pancreas is not particularly sensitive to systemic
hormones. In fact, insulin-​mediated glucose uptake
contributes little to TCA intermediates in mouse pan-
creas. Instead, fatty acids and ketone bodies are used
more readily, especially in times of fasting25. Despite
these findings, systemic insulin has been shown to pro-
mote the formation of precancerous lesions in the mouse
pancreas108. These data suggest that the role of insulin in
pancreas tumorigenesis may be independent of its ability
to stimulate glucose uptake.
Mutations in KRAS are common in human pancreatic
ductal adenocarcinomas (PDACs), and these tumours
have several familiar and several unique metabolic
features that may prove to be targetable vulnerabilities.
For example, in vitro labelling and mouse tumour genetic
analyses indicate enhanced glucose uptake, flux through
glycolysis and diversion of carbon into the hexosamine
and pentose phosphate pathways in these tumours109.
However, studies in KRAS-​driven PDAC cells and mouse
models show that these tumours have increased reliance
on glutamine anapleurosis through a non-​canonical enzy-
matic pathway110. Also, in an apparent exception to the
trend of tumours sharing metabolic preferences with
their tissue origins, BCAA consumption is decreased in
PDACs relative to normal pancreas in mice37,106. In vitro
and mouse studies suggest that KRAS-​driven PDAC cells
rely on scavenging extracellular amino acids via macro­
pinocytosis, in contrast to KRAS-​driven tumours of the
lung, as discussed above37,102,111,112. Mouse models and
epidemiological data also suggest that fatty acid uptake
from the serum is an important feature of PDAC and
pre-​malignant cells in the pancreas. For example, in vitro
lipid labelling studies as well as gene expression analysis
of mouse tumours show that RAS-​transformed pan­
creatic cells avidly consume unsaturated fatty acids from
their environment, potentially as a way to circumvent
hypoxia-​induced inhibition of stearoyl-​CoA desaturase
(SCD)113,114. Dietary interventions limiting unsaturated
fatty acid availability slow tumour growth in mice bear-
ing PDAC allografts, and may be viable therapeutic
options in humans115.
Intestine. The intestinal epithelium is exposed to large,
periodic fluctuations in nutrients based on the quantity
of food intake and the activity of resident microbiota.
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Traditionally, the intestine has been seen as mainly a
transporter of dietary nutrients, but recent work has
highlighted its more active role in metabolism. For
example, the mouse intestinal epithelium converts low
doses of dietary fructose into glucose and organic acids
that are subsequently delivered to the portal blood
and liver27. In vivo labelling studies in mice and pigs
also show that the intestines are the primary site for
production of the body’s short-​chain fatty acids such
as propionate, butyrate and acetate, which are mainly
generated by gut microbiota97,116. In addition to pro-
ducing nutrients for the body, the intestines consume
circulating nutrients such as glucose and glutamine.
In fact, mouse and porcine labelling studies also show
that the small intestine is one of the primary sites of
glucose disposal in the fed state and of ketone body
oxidation while fasting25,97.
Colorectal cancer (CRC) is the most common cancer
arising from the intestine, and its metabolism reflects
its driving mutations, nutrient availability and tissue of
origin. Most CRCs arise from sporadic mutations in the
WNT, PI3K and KRAS pathways13–15. WNT signalling
is hyperactive in 93% of CRC tumours and is associated
with impaired oxidative metabolism, increased pentose-
phosphate pathway (PPP) flux and increased fatty acid
synthesis in in vitro studies, mouse xenograft models
and human tumour samples117,118. PI3K pathway muta-
tions confer a dependence upon glutamine uptake
and metabolism, which have been effectively targeted
to reduce tumour growth in mouse models119,120. KRAS
mutations confer enhanced glucose transporter expres-
sion and improved cell survival in low-​glucose con-
ditions in human CRC-​derived cell lines and mouse
xenograft tumours121. Emerging evidence suggests that
CRC tumours can also directly transport and metabo-
lize fructose from the diet: consumption of moderate
amounts of fructose enhances intestinal tumour
growth in mice by amplifying the expression of hypoxia
response genes. Fructose’s effect on tumour growth
can be negated by targeting the fructolytic enzyme,
ketohexo­kinase (KHK), or the glycolytic enzyme pyru-
vate kinase isoform M2 (PKM2), which plays a critical
role in mediating hypoxia signalling122,123.
Liver. The pancreas and intestines drain into a pool
of venous blood that is directly filtered and sampled
by the liver. This unique anatomy makes the liver a
nutrient-​rich and growth factor-​rich environment ideal
for meta­static growth and tumorigenesis. For example,
the liver is exposed to high levels of fructose, lactate
and organic acids from the small intestine, and insulin
from the pancreas, as compared with other tissues25,27,116.
The liver is also hormone-​sensitive, and studies of the
transcriptional profile of mouse livers over time show
high rates of uptake and production of various metab­
olites depending on circulating hormones as well as
cell-​intrinsic circadian signals124. For example, stable
isotope labelling studies in pigs show that the liver takes
up circu­lating fatty acids (primarily unsaturated), amino
acids and lactate, and releases glutamate and ketone
bodies in response to the low insulin and high glucagon
state induced by fasting97. The liver is also one of the few
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Ketosis
tissues capable of generating and releasing glucose via
A metabolic state defined gluconeogenesis and is the main source of circulating
by low levels of insulin, high glucose in fasted mice25.
hepatic fatty acid oxidation Hepatocellular carcinoma (HCC) is the most common
and increased levels of
circulating ketone bodies.
primary tumour in the liver, and its development and
progression are closely related to nutrient intake
and systemic metabolism. HCC typically evolves grad-
ually from chronically diseased liver tissue such as in
the setting of non-​alcoholic fatty liver disease (NAFLD),
which is estimated to affect up to one-​third of the adult
population globally125. As a result, much attention has
been paid to the systemic and local metabolic altera-
tions contributing to the development of NAFLD and
its progression to HCC. For example, epidemiological
studies in the past two decades have shown that obe-
sity and the metabolic syndrome confer an increased
risk of NAFLD and its progression to HCC126. Diets
associated with obesity such as those high in both fat
and fructose also promote HCC in chemically induced
mouse models127,128. Mechanistically, de novo lipogenesis
(DNL) is purported to play an important role in the pro-
gression from NAFLD to HCC. The exact sequence of
events linking DNL and HCC is still debated, although
one theory posits that increased uptake and genera-
tion of lipids by hepatocytes contribute to a setting of
chronic liver inflammation that selects for progenitor
HCC cells125,129. Indeed, a recent study showed that rats
with an activating mutation in the de novo lipogenic
enzyme, acetyl-​C oA carboxylase (ACC), when fed a
high-fructose diet, exhibited increased hepatic carcino-
genesis as well as tumour cell proliferation. Moreover,
an ACC inhibitor effectively reduced tumour prolif-
eration in the rats and in human tumour-​derived cell
lines130. One substrate that HCCs use for lipogenesis is
glucose, and similar to other cancers, HCCs generally
upregulate glycolysis, although human imaging studies
show that glucose uptake is highly variable and certain
tumours prefer to use alternative nutrient sources such
as acetate131,132.
Box 1 | Dietary interventions as adjuncts to radiotherapy
One particularly promising application of dietary interventions in cancer is to
enhance the efficacy of other therapies such as radiation. Radiation may induce
distinct dietary susceptibilities that are absent in untreated tumour cells. Because
radiation is typically delivered over a set period of time, dietary interventions can
be confined to the treatment window, potentially allowing for improved compliance
and/or a more aggressive intervention.
One mechanism by which diet could improve radiation outcomes is by limiting the
ability of tumour cells to recover from DNA damage. For example, in patient-​derived
and autochthonous tumour mouse models, a methionine-​restricted diet sensitized
tumour cells to radiation via changes in one-​carbon metabolism. A similar dietary
approach was adapted for humans in a controlled clinical study, although the effects
on tumour outcomes have yet to be evaluated229.
Diets that lower circulating glucose have also been investigated as adjuncts to
radiation. For example, in mouse models of lung and brain cancer, low glucose cell
culture conditions or ketosis-​inducing low-​carbohydrate diets specifically increase the
susceptibility of tumour cells to radiation230–232. More recently, in a small, randomized
trial of recurrent malignant glioma in humans (ERGO2), a very low carbohydrate diet
(VLCD) combined with intermittent fasting was examined as an adjunct to radiation
therapy. The study did not show a statistically significant difference in progression-​free
survival or overall survival with the diet, but the 9-​day intervention was well tolerated
and post hoc analysis showed that patients who were able to achieve lower levels of
circulating glucose by day 6 had significantly improved survival233.
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Microbiome
In addition to the typical macronutrients studied in
the context of other tumours, the intestine and liver
have unique exposures to dietary, microbial and
gastrointestinal-​secretory products that must be consi­
dered. For example, mouse studies reveal that high-​fat
diets can promote microbiota species that increase the
amount of tumour-​promoting bile acid species in
the intestine133. Additional studies in germ-​free versus
conventionally housed mice reveal that the short-​chain
fatty acid butyrate, produced by microbial metab­olism
of dietary carbohydrate in the intestine, is a major
energy source for differentiated colonocytes134. Although
butyrate production can be modulated by dietary
interventions, existing mouse studies offer conflicting
indications about whether such interventions would
be desirable therapies for CRC, and more studies are
needed135,136. Microbial short-​chain fatty acids are also
important substrates for the liver. For example, recent
tracing studies in mice reveal that dietary fructose serves
as both a signal and a substrate for hepatic lipogenesis,
in part through its conversion to acetate by gut-​resident
microbiota116. Global gene expression profiling of human
HCCs also identified a subset of aggressive tumours that
may rely on gut-​derived acetate for fatty acid synthesis,
presenting a promising population for dietary and/or
microbial interventions137. Beyond these few examples
of microbial-​influenced nutrient availability for tumours,
there are a plethora of studies available in preclinical
models reporting associations between the microbiome
and cancer initiation, growth and response to therapy,
which are covered in excellent reviews elsewhere138.
Because elements of the microbiome are clearly influ-
enced by diet, such mechanistic associations between
the microbiome and cancer present attractive targets
for dietary interventions in human studies.
Systemic effects of dietary therapies
Dietary interventions could potentially improve tumour
therapy in several ways. For example, diets can elimi-
nate specific nutrients that tumours use as fuel. They
can also potentiate other forms of therapy, such as
radiotherapy (Box 1) and chemotherapy, by depriving
tumours of escape nutrients and signals. Diets can also
act secondarily, modulating the abundance of growth
factors or altering the systemic immune state to affect
tumour growth and the antitumour immune response,
respectively10.
Dietary interventions come in various forms139. Some
focus on content, such as energy (caloric) restriction or
macronutrient manipulation, whereas others are defined
by timing, such as intermittent fasting regimens that
impart intervals of complete or partial energy restric-
tion, regardless of meal composition. As these inter-
ventions have long been utilized in the fields of obesity
and diabetes, we include a brief review of these stud-
ies to help identify the potentially beneficial metabolic
responses that may occur in patients with cancer. For
example, studies in subjects with obesity have shown that
any dietary intervention with a caloric deficiency will
activate a neurohormonal response leading to weight
loss, a decrease in insulin and leptin levels, activation
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Metabolic dysfunction
of lipolysis in adipose tissue and reduced blood glucose
A general term collating variability139.
multiple abnormalities in
glucose and lipid homeostasis Calorie restriction
such as dyslipidaemia, obesity,
insulin resistance, glucose
Calorie restriction reduces the total daily energy intake
intolerance, diabetes and while maintaining a well-​b alanced macronutrient
fatty liver disease. ratio. In most clinical applications, subjects reduce
their caloric intake by 15–30%. This amount of calorie
restriction lowers body weight, fat mass, insulin, thyroid
hormones and the metabolic rate in adults with
overweight140–142. These findings persist at 6 months and
2 years of intervention141,143, and also occur in subjects
with obesity with pre-​existing metabolic dysfunction144,145.
In studies of calorie restriction, dropout rates of 30–40%
can be achieved when all foods are provided and par-
ticipants are highly motivated146,147. Calorie restriction
is typically well tolerated with few unexpected adverse
events148.
Since the early 1900s, researchers have observed the
beneficial effects of calorie restriction in mouse tumour
models149. In addition to reducing tumour incidence in
mice, calorie restriction slows the progression of can-
cer and the incidence of metastasis150. For example,
calorie restriction provides greater protection against
established breast and intestinal tumour growth and
metastasis151,152. The mechanism by which calorie restric-
tion could improve tumour outcomes is pleotropic.
Calorie restriction reduces insulin, which lowers tumour
PI3K signalling153. Calorie restriction also promotes
bene­ficial changes in the immune signature151, activation
of antioxidant pathways154 and beneficial reductions in
circulating unsaturated fats115.
There are limited human data describing the effects
of calorie restriction as an anticancer intervention148.
Short-​term studies show that it does not increase grade 3
or 4 adverse events during chemotherapy, suggesting cal-
orie restriction is safe155,156. In 2007, a phase III trial was
initiated to test the effect of calorie restriction and exer-
cise (administered as the Diabetes Prevention Program)
on disease-​free survival and overall survival in postmen-
opausal women with breast cancer. Unfortunately, the
accrual was terminated early owing to loss of funding and
only 338 of the planned 2,150 women were enrolled. The
available data were promising, showing a small (~4%) but
Box 2 | Time-​restricted feeding
Time-​restricted feeding is another fasting-​based approach that is emerging as a
potential anticancer intervention. Time-​restricted feeding prolongs the daily fasting
period to at least 14 h. In subjects without cancer, time-​restricted feeding has produced
mixed results in terms of weight loss and improvements in metabolic markers234–239.
Interestingly, the clinical data suggest that the metabolic response depends on the
time of day of the eating window240. Restricting food intake to the middle of the day
(early time-​restricted feeding) may be better than late afternoon or evening periods241.
Early time-​restricted feeding results in nearly 100% compliance with no adverse
events240.
Time-​restricted feeding abrogates obesity-​enhanced mammary tumour growth in
two orthotopic mouse models in the absence of calorie restriction or weight loss242.
Time-​restricted feeding also reduces rates of tumour metastasis in mice242,243. By phar-
macologically increasing or decreasing tumour insulin exposure, the authors found that
the primary effect of time-​restricted feeding is via a reduction in hyperinsulinemia242.
To our knowledge, no trials of time-​restricted feeding have been initiated in patients
with cancer.
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significant weight loss at 2 years with only a 22% dropout
rate and a trend towards improved disease-​free survival
(hazard ratio 0.71, 95% confidence interval 0.41–1.24,
P = 0.23)157,158. Therefore, we eagerly await the results of
the Breast Cancer WEight Loss Study (BWEL Study),
a randomized phase III trial evaluating calorie restriction
as an adjuvant treatment for early breast cancer159.
Fasting mimicking diets
During calorie restriction interventions, the period
of fasting between meals is a commonly ignored con-
founding variable. Mice undergoing calorie restriction
will consolidate food intake into a single meal leading
to an intermittent, large influx of calories spaced by long
periods of fasting and hyperactivity160. This adaptation
has led some to question whether it is the calorie restric-
tion, per se, or the fasting period that mediates the bene­
fits of calorie restriction in mouse models. In carefully
controlled studies in mice comparing calorie restriction
with fasting interventions that provide a normal amount
of calories in one meal per day, fasting results in simi-
lar improvements in health and survival, regardless of
caloric intake, diet composition and bodyweight161,162.
In small clinical studies of subjects with cancer under-
going chemotherapy, fasting lowered pro-​tumorigenic
hormones, reduced adverse events and improved quality
of life163,164. Fasting also alters the abundance of periph-
eral immune cells such as monocytes and a subset of
dendritic cells, which may have beneficial antitumour
effects165. However, prolonged periods of fasting are hard
to maintain166. Therefore, several regimens of intermit-
tent fasting have been designed to mimic the benefits of
fasting and improve long-​term adherence167. One such
programme is the fasting mimicking diet (FMD) where
subjects undergo cycles of consuming calorie-​restricted,
low-​carbohydrate, low-​protein diets for four or five
consecutive days each month. For example, FMD may
consist of a 5-​day, plant-​based diet comprising up to
600 calories on day 1 and up to 300 calories on days 2–5
(ref.16). The food is not restricted during the remainder of
the month, so participants get a long break between FMD
cycles. In a randomized crossover study of 100 healthy
subjects, 3 FMD cycles reduced body weight and total
body fat, lowered blood pressure, and decreased blood
insulin and IGF1 levels as compared with the standard
diet168. The intervention was safe with no grade 3 or 4
adverse events and a dropout rate (25%) that was better
than calorie restriction intervention trials. When com-
pared head to head with calorie restriction in a ran­
domized controlled trial of 60 obese women, 2 months
of FMD led to similar weight loss and improvements
in markers of insulin resistance and muscle mass,
albeit these were not measured using gold-​standard
methods169. Other forms of intermittent fasting, such as
time-​restricted feeding, are under investigation (Box 2).
In mouse models of cancer, cycles of fasting reduce
tumorigenesis and slow tumour growth170–173. When
paired with traditional anticancer therapy, FMD cycles
can enhance therapeutic efficacy. For example, fast-
ing cycles enhance gemcitabine efficacy in mice with
prostate cancer xenografts174, and the FMD strategy
leads to durable remission of breast tumours in mice
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Preclinical Safety/feasibility Efficacy Clinical practice

Low fat NCT04298086

Calorie restriction NCT02750826

Very low carbohydrate NCT05090358

Fasting mimicking NCT04248998

Amino acids NCT05183295

Fig. 3 | Development progress for dietary interventions for cancer. Several dietary interventions are advancing
well along the clinical development pipeline, with specific example trials highlighted. Based on evidence primarily in
subjects with breast cancer, low-​fat diet (LFD) is often recommended to patients with cancer211–213. Calorie restriction is
safe in subjects with cancer, yet a high dropout rate and poor funding have limited formal efficacy studies157,158. Very low
carbohydrate diet (VLCD) and fasting mimicking diet (FMD) are rapidly advancing through safety and feasibility studies,
and efficacy trials are on the horizon in subjects with cancer16,183. Time-​restricted feeding and diets depleted in specific
amino acids have shown efficacy in mouse models, but limited clinical data are available11.

when combined with anti-​o estrogen therapy and
cyclin-​dependent kinase 4 (CDK4) and CDK6 (hereafter
CDK4/6) inhibition, a clinically relevant combination13.
The beneficial effects of FMD are dependent on low
levels of insulin, leptin and IGF1; when these hormones
are co-​administered to mice receiving FMD, the diet’s
antitumour effects are abolished13.
FMD is a promising clinical intervention that is rapi­
dly advancing along the clinical development pipeline
(Fig. 3). In most cases, FMD is safe and feasible with rates
of grade 3 or 4 adverse events of 13% and dropout rates of
24% after 3 FMD cycles in subjects with cancer13,16,175.
The beneficial metabolic effects on insulin, IGF1 and
leptin observed in mice appear to be conserved in sub-
jects with cancer while preserving body weight13,15,16,171,175.
These changes lower immunosuppressive peripheral
cells and enhance the intratumour cytotoxic response16.
Moreover, FMD is safe in combination with a CDK4/6
inhibitor and may improve efficacy13. We eagerly await
more clinical studies with formal tumour outcomes176.
Very low carbohydrate (ketogenic) diets
Some of the systemic metabolic benefits of calorie
restriction and fasting can be recapitulated by diets with
altered macronutrient ratios. For example, very low
carbo­hydrate diets (VLCDs) or low-​fat diets (LFDs)
suppress food intake and alter tumorigenic hormones,
as compared with standard diets177,178. These diets have
been studied in patients with cancer for decades, showing
adequate safety, feasibility and, in some cases, anticancer
efficacy data.
The VLCD was clinically described in the 1920s as
a means of sustaining the epilepsy-​alleviating effects of
fasting179,180. In this ‘classic’ form, the VLCD has very
low carbohydrate intake of ≤15 g per day (<5% of calo-
ries), a moderate to low protein intake and enough fat to
make up the rest of the calorie expenditure181. Typically,
the fats arise from coconut oil, butter, eggs, avocados,
cheese and meat. This style of eating has been shown to
promote and maintain very low levels of serum insulin
in children with epilepsy, adults with obesity with meta-
bolic syndrome and patients with cancer182–186. Because
of the lack of carbohydrates and glycaemic load, VLCDs
are more effective in improving metabolic parameters
associated with glycaemic, weight and lipid controls in
patients with high body mass index, especially those
with pre-​existing diabetes, as compared with LFDs187.
The long-​term effects of eating a VLCD have not been
evaluated in large, prospective, randomized controlled
clinical trials; however, there is supportive evidence of
safety. In a non-​randomized study of participants with
type 2 diabetes over 2 years, an intervention including
telemedicine, health coaching and a personalized VLCD
improved metabolic markers with no reported adverse
events and a 26% dropout rate188. In patients without
obesity or metabolic disease, the diet may cause low-
grade fatigue, headache, nausea, constipation, hypo-
glycaemia and acidosis within the first few days to
weeks189,190. Low-​grade dehydration, hepatitis, pancrea-
titis, hypertriglyceridemia, hyperuricaemia, hypercho-
lesterolaemia, hypomagnesaemia and hyponatraemia
have been reported in older people191.
Despite the potential for adverse events, a syste­
matic review of 13 studies using a VLCD in subjects
with various cancers concluded that this approach is
safe, especially when compared with traditional anti-
cancer therapy192. For example, Cohen et al. performed
a 12-​week randomized controlled trial in women with
ovarian or uterine cancer to test the effects of a VLCD
intervention on metabolic parameters183. Adherence
to the diet was excellent (dropout rate 19%), and there
were only low-​grade adverse events including hunger,
constipation, fatigue, muscle cramps, diarrhoea and
cold extremities. Subjects displayed selective loss of fat
mass, retention of lean mass and no change in blood
lipids182,183,193. Importantly, those on the VLCD had sig-
nificantly lower measures of insulin production and
higher physical function scores193. No effects on tumour
outcomes have been reported from this cohort. In other
situations, the VLCD is not well tolerated. For example,
only 4 of 12 subjects with locally advanced head and neck
cancer could complete a 5-​week VLCD intervention,
and several adverse events were noted including grade 2
nausea, grade 3 fatigue, grade 4 hyperuricaemia and

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Table 1 | Potential dietary and pharmacological pairings for future study

Tissue type Tumour or host notable growth Potential dietary Potential pharmacologic Preclinical
biomarkers substrates interventions partners evidence
Breast PIK3CA mutation Glucose VLCD or FMD PI3K–mTOR pathway or ER inhibitor 12,13,69,71,73,83

Triple-​negative Glucose or fatty acids LFD or FMD CDK4/6 or EGFR inhibitor 80,173,226

PHGDH elevation Serine Serine and PHGDH inhibitor 78

glycine-​depleted diet
Endometrial PI3K–mTOR pathway Glucose VLCD PI3K–mTOR pathway inhibitor 6,12,86,87

activation
Prostate MYC pathway activation Fructose or fatty acids LFD, calorie restriction DNL pathway inhibitor 88–92,222

or FMD
Lunga KRAS mutation BCAAs, ketones, fructose Unknown Immunotherapy or chemotherapy 37,102,106,227

or lactate
Pancreasa KRAS mutation Fatty acids Calorie restriction SCD inhibitor or chemotherapy 108,115

or VLCD with high

saturated fatty acids
Intestine WNT pathway activation Glucose or fatty acids LFD DNL inhibitors or chemotherapy 119,123,133

SLC2A5 or KHK Glucose or fructoseb Low-​sugar diet KHK inhibitors, DNL inhibitors 122,123

elevation or chemotherapy
Liver Microbiome alterations Fructose, fatty acids or LFD DNL pathway inhibitor 116,126–128,130–132

short-​chain fatty acids

Brain IDH mutation Glutamine, serine or VLCD or serine and PI3K–mTOR pathway or PHGDH 55,58,59,61,223,228

acetate glycine-​depleted diet inhibitor

BCAA, branched-​chain amino acid; CDK4/6, cyclin-​dependent kinase 4 (CDK4) and CDK6; DNL, de novo lipogenesis; EGFR, epidermal growth factor receptor;
ER, oestrogen receptor; FMD, fasting mimicking diet; IDH, isocitrate dehydrogenase; KHK, ketohexokinase; LFD, low-​fat diet; PHGDH, phosphoglycerate
dehydrogenase; SCD, stearoyl-​CoA desaturase; SLC2A5, solute carrier family 2 member 5; VLCD, very low carbohydrate diet. aHigh risk for weight loss so diets
imposing a calorie restriction should be used with caution. bAlso used as a growth signal.

Response Evaluation
Criteria in Solid Tumours
(RECIST). A validated
and consistent radiologic
methodology to evaluate the
activity and efficacy of new
cancer therapeutics in solid
tumours.
grade 3 acute pancreatitis194. The VLCD is also poorly
tolerated in subjects with lung and pancreatic cancer. For
example, only 3 of 9 subjects with these cancers could
comply with the diet over 2 years195. Patients with head
and neck, lung and pancreas cancers have a high risk of
developing cachexia196, which may be limiting the ability
to comply with a VLCD.
There is growing enthusiasm for the use of the VLCD
as an anticancer intervention. A dietary pattern lower
in carbohydrates and protein, and higher in fat is asso­
ciated with longer survival time in patients with pancre-
atic cancer115. However, it remains unclear whether these
patients will be able to tolerate this dietary pattern given
the high predilection for weight loss197. This question
is currently under investigation198. There are also pro­
mising data for use of the VLCD in women with breast
cancer. In a randomized controlled trial in 80 subjects
with breast cancer undergoing chemotherapy, a 12-​week
VLCD intervention reduced the tumour diameter as
compared with the controls on a standard diet199. We
interpret these results with caution as the Response
Evaluation Criteria in Solid Tumours (RECIST)200 were not
used to measure tumour size and dietary fat intake is asso­
ciated with increased risk for breast cancer development
and recurrence in certain subgroups201–205. Nevertheless,
these are exciting preliminary data that support the need
for future studies to better define the specific patient
subsets that will most benefit from the VLCD.
Low-​fat diets
LFDs restrict fat intake to less than 30% of total calories
per day and emphasize intake of vegetables, fruits and
whole grains. LFDs safely promote weight loss, fat loss,
lower blood cholesterol and reduced food intake in sub-
jects without cancer206. In fact, several LFDs are endorsed
by major medical associations including the Dietary
Approaches to Stop Hypertension (DASH) diet, the US
Department of Agriculture food pattern, a vegan diet
and the American Heart Association (AHA) diet207–210.
Unlike the other dietary interventions discussed in
this Review, LFDs have been rigorously tested in large
populations of subjects with cancer. The Women’s
Health Initiative Dietary Modification (WHI DM)
trial was a prospective, randomized controlled study
in postmenopausal women designed to examine the
long-​term benefits and risks of a LFD on breast can-
cer, CRC and cardiovascular disease203,211. Although no
long-​term reduction in cancer risk or overall mortality
was observed212, the LFD intervention lowered the inci-
dence of deaths after breast cancer diagnosis203. This
finding was more directly assessed in two randomized
trials: the Women’s Intervention Nutrition Study (WINS)
and the Women’s Healthy Eating and Living (WHEL)
study. Both were randomized trials to test the effects of
a LFD intervention in women with previously treated,
early-​stage breast cancer204,205. Both trials achieved about
a 9% reduction in dietary fat intake between intervention
and control groups with about a 30% dropout rate after
3 years213. Although there were some notable differences
in the populations studied and outcomes reported213, the
WINS and WHEL data suggest that LFDs have beneficial
effects only in subgroups of patients with breast cancer.
For example, there was a diet-​induced reduction in distal
recurrences among women who did not experience hot
flashes214. This benefit may be due to the diet’s ability
to reduce oestradiol concentrations215,216, which may be

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One-​carbon metabolism
irrelevant in the age of ER blockade. This question is
Referring to both the folate currently under investigation217.
and methionine cycles that In regard to prostate cancer, the benefits of a LFD are
allow cells to generate less clear. Diets high in fat and saturated fat induce a MYC
one-​carbon units for the
gene expression signature that independently predicts
biosynthesis of important
anabolic precursors and prostate cancer progression and death218. This finding
for methylation reactions. has led researchers to study the LFD in several cohorts
of men with prostate cancer. Despite good adherence, the
Eastern Cooperative diet does not change serum prostate-​specific antigen, sex
Oncology Group
(ECOG). A standardized
hormones, insulin or IGF1 in this setting219–221. Tumours
clinical scoring algorithm that may evade the effects of a LFD by upregulating fatty
describes a patient’s level of acid synthesis so clinical efficacy might be improved by
functioning in terms of their combining a LFD with inhibitors of this pathway222.
ability to care for themself,
daily activity and physical
ability (walking, working and Other dietary interventions
so on). There are numerous other means to modify the diet that
might impede tumour growth. For example, depletion of
Subjective Global specific amino acids such as serine and glycine, cysteine
Assessment
(SGA). A clinical scoring
and methionine show promising anticancer efficacy in
algorithm using information preclinical models (nicely reviewed elsewhere11), but
from a patient interview and there are no clinical data yet. Restricting these amino
physical examination that acids in preclinical models depletes tumours of neces-
healthcare providers use
sary precursors for one-​carbon metabolism, and thereby
to determine a person’s
nutritional status. inhi­bits established tumour growth223. Furthermore, the
addition of certain sugars, vitamins and amino acids to
the diet may alter nutrient flux and enhance antican-
cer therapy (recently reviewed in detail10). Early-​phase
clinical studies are ongoing for many of these approaches.
Towards precision nutrition for cancer
Precision medicine promises to deliver the right drug
to the right patient at the right time. This approach
is helping transform the treatment of cancer from
Box 3 | recommendations for dietary intervention studies in cancer
• Provide all meals to support subject adherence.
• Carefully engineer meal plans in collaboration with an experienced dietician and
openly report these details139. Key pieces of information are often missing from
published studies and this deficit limits rigor and reproducibility. Studies should
include the following.
-- Food weight and energy density.
-- Macronutrient and micronutrient content.
-- Source of the food products.
-- Fasting duration and timing between fasts.
• Define appropriate exclusion criteria focused on key effects of the diet intervention.
-- Subjects with cachexia, anorexia or moderate-​to-​severe protein-​calorie
malnutrition may not tolerate diets that impose a large calorie restriction. These
patients may be screened for using exclusion criteria such as body mass index
(BMI) < 20 kg/m2, Eastern Cooperative Oncology Group (ECOG) performance
status ≥3, bioimpedance phase angle <4.5° or Subjective Global Assessment (SGA)
category B/C.
• Assume dropout rates of 20–30% of subjects and power appropriately.
• Collect and report pertinent molecular features of the tumour for each subject.
-- Histological and molecular subtype.
-- Genetic alterations.
• Catalogue and report the adverse events using standard methods.
• Pre-​plan appropriate pharmacodynamic read-​outs.
-- Nutrient or hormone measures in the blood and/or tumour tissue.
-- Appropriate changes in signalling pathways in the tumour.
-- Changes in traditional oncological read-​outs such as progression-​free survival and
overall survival.
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one-​size-​fits-​all to bespoke interventions for clearly
denoted cancer subtypes. A similar course could be
taken for delivering dietary interventions to support
cancer therapy. We propose targeting dietary interven-
tions to vulnerable tumour tissue types with distinct his-
tological and molecular features (Table 1). For example,
ER+ breast cancers frequently develop PIK3CA muta-
tions to evade hormonal therapy, as discussed above.
These patients may benefit from combining hormonal
and PI3K inhibitor therapy with a VLCD, which lowers
insulin and reduces the tumour’s ability to maintain rapid
nutrient uptake12,13. By contrast, because triple-​negative
breast cancers may rely more heavily on exogenous fatty
acids, a LFD may be a better intervention80. CRC growth
can be promoted by fructose and dietary fats, and thus
a plant-​based LFD with no added sugar, which has been
shown to be feasible in humans224, may be appropriate
for these patients. Pancreatic cancer cells, meanwhile,
rely on exogenous unsaturated fatty acids, and thus a
calorie-​restricted or VLCD specifically high in saturated
fats may be effective115.
Diet interventions should be paired with synergistic
pharmacological therapies because it is unlikely that diet
alone will be strong enough to combat tumour progres-
sion. For example, data in mice indicate that FMDs and
VLCDs can lead to durable tumour regression when they
are paired with CDK4/6 and PI3K inhibitors, respec-
tively12,13. Mouse studies and human genomic analyses
also endorse the combination of amino acid-​depleted
diets and diets low in unsaturated fats with inhibitors
of metabolic enzymes such as phosphoglycerate dehy-
drogenase (PHGDH) and SCD, respectively115,223. The
ability of calorie restriction and FMD to synergize
with standard-​of-​care chemotherapy is under active
investigation.
The field of precision nutrition is moving at a rapid
pace with numerous pre-​registered trials on the horizon.
We would like to highlight several aspects to consider
when planning a dietary intervention study in patients
with cancer (Box 3). Of note, the field needs to better
identify and catalogue diet-​related adverse events. All
effective anticancer interventions cause toxicity and
the field needs to agree on the amount of toxicity that
is acceptable from a dietary intervention. In a recently
published study16, Vernieri et al. pre-​specified a 20%
threshold for severe (grade 3 or 4) adverse events arising
from a FMD. Given that fasting may help mitigate the
adverse effects of chemotherapy, this seems a reason­
able cut-​off value225. Even with adequate safety, a portion
of subjects do not adhere to prescribed diets, even with
adequate counselling and full menus provided. There are
numerous reasons for this. There are neurohormonal
pathways that strongly regulate behaviour in the set-
ting of weight loss, and food carries sentimental value
in our cultures, serving as a means to connect with loved
ones on special occasions. Investigators should assume
dropout rates of 20–30% during power calculations if the
appro­priate pilot data are not available in subjects with
cancer. Additional studies are needed to find the optimal
time to commence dietary interventions because some
may only be effective in patients with early-​stage can-
cers; we have limited information in this regard. Lastly,
Reviews

we know very little about the effects of dietary inter-
ventions on tumour metabolism, signalling and immu-
nity in humans, and this should be investigated using
appropriate pharmacodynamic read-​outs.
Conclusion
Tumour tissue of origin and genetic driver mutations
contribute to distinct metabolic preferences, which can
be targeted with diet during cancer therapy. There is an
overall impression by the lay press that ‘healthy eating’
will aid in the fight against cancer. Although this senti-
ment is supported by epidemiological data in the setting
of cancer prevention6, it is important to remember that
fighting cancer is a high-​risk, high-​reward endeavour
and the acceptable limits of toxicity need to be balanced
with the potential for a successful outcome. Dietary
intervention studies have relatively high dropout rates
and may impose additional toxicity; however, the promi­
sing preclinical and early clinical data support their
further development. We suggest maximizing the likeli-
hood of success by designing studies that test diet–drug
combination therapies based on the tumour tissue of
origin, genetic alterations and the degree of interaction
with systemic hormones and metabolites. Future studies
should include appropriate pharmacodynamic read-​outs
that catalogue the effects of each diet on tumour growth,
metabolism and microenvironment composition, which
are all understudied in this field.
Published online xx xx xxxx

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Acknowledgements
This work was supported, in part, by National Institutes of
Health (NIH) K08CA230318 (M.D.G.), 2020 AACR–The
Mark Foundation for Cancer Research ‘Science of the Patient’
(SOP) Grant Number 20-60-51-​G ONC (M.D.G.), NIH
R35CA197588 (L.C.C.) and a grant from the Breast Cancer
Research Foundation (L.C.C.).
Author contributions
S.R.T., J.N.F. and M.D.G. researched data for the article and
wrote the article. All authors contributed substantially to
discussion of the content, and reviewed and/or edited the
manuscript before submission.
Competing interests
L.C.C. is a founder, shareholder and member of the scientific
advisory board of Agios Pharmaceuticals and a founder and
former member of the scientific advisory board of Ravenna
Pharmaceuticals (previously Petra Pharmaceuticals). These
companies are developing novel therapies for cancer. L.C.C.
has received research funding from Ravenna Pharmaceuticals
outside the covered work. L.C.C. and M.D.G. are co-​founders
and shareholders of Faeth Therapeutics, which are developing
dietary and pharmacologic therapies for cancer. M.D.G. has
received speaking and/or consulting fees from Pfizer Inc.,
Novartis AG, Petra Pharmaceuticals, Scorpion Therapeutics
and Faeth Therapeutics. M.D.G.’s laboratory has received
financial support from Pfizer Inc. outside the covered work.
All other authors report no competing interests.
Peer review information
Nature Reviews Cancer thanks Stephan Herzig, Ömer Yilmaz
and the other, anonymous, reviewer(s) for their contribution to
the peer review of this work.
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