Download KGMI 16 2341717

GUT MICROBES
2024, VOL. 16, NO. 1, 2341717
https://doi.org/10.1080/19490976.2024.2341717
REVIEW
An emerging strategy: probiotics enhance the effectiveness of tumor
immunotherapy via mediating the gut microbiome
Shuaiming Jiang
a
, Wenyao Maa, Chenchen Mab, Zeng Zhanga, Wanli Zhanga, and Jiachao Zhang
a
a
School of Food Science and Engineering, Hainan University, Haikou, PR China; bDepartment of Human Cell Biology and Genetics, Southern
University of Science and Technology, Shenzhen, PR China
ABSTRACT
ARTICLE HISTORY
The occurrence and progression of tumors are often accompanied by disruptions in the gut
microbiota. Inversely, the impact of the gut microbiota on the initiation and progression of cancer
is becoming increasingly evident, influencing the tumor microenvironment (TME) for both local
and distant tumors. Moreover, it is even suggested to play a significant role in the process of tumor
immunotherapy, contributing to high specificity in therapeutic outcomes and long-term effective­
ness across various cancer types. Probiotics, with their generally positive influence on the gut
microbiota, may serve as effective agents in synergizing cancer immunotherapy. They play a crucial
role in activating the immune system to inhibit tumor growth. In summary, this comprehensive
review aims to provide valuable insights into the dynamic interactions between probiotics, gut
microbiota, and cancer. Furthermore, we highlight recent advances and mechanisms in using
probiotics to improve the effectiveness of cancer immunotherapy. By understanding these com­
plex relationships, we may unlock innovative approaches for cancer diagnosis and treatment while
optimizing the effects of immunotherapy.
Received 29 January 2024
Revised 31 March 2024
Accepted 8 April 2024
CONTACT Wanli Zhang
Haikou 570228, PR China
[email protected]; Jiachao Zhang
[email protected]
KEYWORDS
Probiotics; tumor
immunotherapy; gut
microbiome; tumor
microenvironment; tumor
microbiome
School of Food Science and Engineering, Hainan University,
© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been
published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
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S. JIANG ET AL.
1. Introduction
The complex interplay between the gut microbiota
and human well-being has recently emerged as
a captivating area of research. Tumors arise and
progress in individuals with compromised immune
function, where the immune system fails to recog­
nize and eliminate abnormal cells. This process is
also accompanied by disturbances in the gut
microbiota.1 Numerous studies have shown nota­
ble variations in gut microbiota between healthy
individuals and cancer patients, with unique
microbial signatures observed among various can­
cer groups. Inversely, the impact of the gut micro­
biota on the onset and growth of cancer is
increasingly clear,2,3 affecting the tumor microen­
vironment (TME) and impacting both local and
distant tumors (Figure 1). Tumor immunotherapy
is an approach to treatment that stimulates the
body’s tumor-specific immune responses to har­
ness their inhibitory and cytotoxic functions
against cancer cells, which has been rapidly devel­
oped and garnered attention due to its high speci­
ficity and potential for long-term effectiveness.4
However, the major limitation of tumor immu­
notherapy is that it does not work for all cancer
patients. Substantial evidence has demonstrated
that among various types of cancer, some indivi­
duals may not show significant treatment
responses to ICIs and have side effects due to
intestinal microorganisms.5
Within this context, as beneficial microorganisms,
probiotics have drawn attention for their ability to
modulate the gut microbiota and hold promise in
potentially alleviating various health conditions and
diseases.6,7 Probiotics also modulate intestinal
immune function by interacting with various cell
types, including IECs, dendritic cells (DCs), T cells,
and B cells, influencing their differentiation, activa­
tion, proliferation, and secretion.8–11 In addition, they
also play a crucial role in enhancing cancer immu­
notherapy and providing better inhibition of tumor
growth. On the one hand, probiotics can regulate the
gut microbiota and immunity, influencing the body’s
response to immune inhibitors. On the other hand,
probiotics can also translocate to tumor sites and
exert their inhibitory effects.12–15
Therefore, this manuscript explores the inter­
play between the gut microbiota and the TME.
We summarize the disturbance of the intestinal
microbiota in cancer patients and potential under­
lying causes, as well as the microbial biomarkers
that can be used for the diagnosis and prognostic
assessment of cancers.16–18 We also investigated
how the gut microbiota affects the tumor micro­
environment, including the composition of the
tumor microbiota and its influence on cancer
development. Furthermore, we highlight recent
advances in using probiotics to improve the effec­
tiveness of cancer immunotherapy. This compre­
hensive review aims to provide valuable insights
into the dynamic interactions between probiotics,
gut microbiota, and cancer. By understanding these
complex relationships, we may unlock innovative
approaches for cancer diagnosis and treatment
while optimizing the effect of immunotherapy.
2. Gut microbiome and probiotics
The gut microbiota, consisting of a large number of
microorganisms, has garnered widespread atten­
tion for its multifaceted role in human health.
These microorganisms, predominantly anaerobic
bacteria, are roughly equivalent in number to
human cells,19 with their unique genes exceeding
the human genome by approximately 100-fold.20
The gut microbiota contributes to food digestion
and nutrient absorption, engages in diverse meta­
bolic processes, and profoundly impacts host
immunity maintenance and regulation.21
Consequently, overall health needs to maintain
the balance of the gut microbiota. Diet, geography,
and health status have the most remarkable effects
on gut microbiota composition. In general, it
remains in dynamic equilibrium; once the balance
of the gut microbiota is disturbed, it can cause the
host to lose various functions, including barrier
function, immunological function, and inflamma­
tion, which makes it harder to fight pathogens,22
thereby inducing various diseases, such as inflam­
matory bowel diseases;23,24 metabolic disorders,
such as obesity and type 2 diabetes;25–27 autoim­
mune diseases,28,29 such as food allergies,30
eczema,31 and asthma;32 and even the growth and
incidence of malignancies (Figure 1).33,34 In addi­
tion, growing interest in the significance of the gut
GUT MICROBES
3
Figure 1. The healthy gut and various diseases that may be caused by gut dysbiosis.
microbiota in disease states has garnered increasing
attention, as it can extend beyond the intestinal
barrier and impact primary lymphoid organs and
the tumor microenvironment.35–38 In tumor
immunotherapy research, only a subset of partici­
pants demonstrates a significant response, imply­
ing that the intestinal microbiota is crucial in
tumor immunotherapy.
By intervening in the gut microbiota, probiotics
can potentially enhance the host’s well-being and
improve the host’s health. Probiotics exert their
pleiotropic effects to reduce potential disease risks
by employing several key mechanisms by competi­
tively excluding harmful microbes, producing ben­
eficial metabolites, including short-chain fatty
acids,39,40 hydrogen peroxide,41 and bacteriocin,42
regulating immunity, and maintaining the integrity
of the mucosa.43 Numerous studies have revealed
that probiotics can help prevent and treat gastro­
intestinal diseases,44,45 chronic metabolic
diseases,46,47 and cardiovascular and cerebrovascu­
lar diseases.48–50 In recent years, some studies have
applied probiotics in tumor immunotherapy and
found that probiotics can cooperate with tumor
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S. JIANG ET AL.
immunotherapy to achieve better tumor suppres­
sion effects. This also suggests a brighter prospect
for using probiotics in treating and preventing
diseases.
3. The gut microbiome and cancer
Multiple studies have shed light on the gut micro­
biota’s function in promoting or inhibiting tumor
development.51 The interaction between microor­
ganisms and cancer is multifaceted. Microbes can
contact cancerous tissues directly, influencing
their behavior.52,53 Additionally, microbes could
indirectly affect cancer, including the modulation
of host physiology or the induction of systemic
inflammation by the gut microbiota, affecting
tumors’ spread to distant places.51,54 When diet­
ary or host-released metabolites enter the gut,
they undergo biotransformation through micro­
bial catalysis.55 These metabolites can reach
remote tissues upon absorption and circulation
within the host and influence tumor
progression.56 Both individual microbial species
and the overall microbial community contribute
to tumor initiation and development. For
instance, Helicobacter pylori, initially identified
as the causative agent of gastritis, has
a significant correlation with gastric cancer
epidemiologically.57 Gastric cancer risk was con­
siderably decreased following the elimination of
H. pylori. Meanwhile, tumors arise and progress
in individuals with compromised immune func­
tion, where the immune system fails to identify
and eliminate abnormal cells;1 these effects occur
alongside disturbances in the gut microbiota.
3.1. Characteristics of the gut microbiome in
patients with various types of cancer
Numerous studies have shown notable variations
in the gut microbiota composition between healthy
subjects and cancer patients. Moreover, within dif­
ferent groups of cancer patients, there may be
unique microbial signatures (Table 1).
With a troubling rise in occurrence among
young adults over the past 20 years, colorectal can­
cer (CRC) has risen to the third most common
cancer among all cancers worldwide.115
Numerous studies have illuminated the complex
interaction between the gut microbiota and the
emergence of CRC. Moreover, certain members
of the microbial population have been linked to
colorectal cancer. Animal models used in func­
tional investigations have identified several micro­
organisms, including Escherichia coli, Enterococcus
faecalis, Fusobacterium nucleatum, and Bacteroides
fragilis, and demonstrated their potential carcino­
genic roles in colorectal cancer development.116
B. fragilis can produce B. fragilis toxin (BFT),
which triggers inflammatory responses and the
abnormal proliferation of intestinal cells.66
Enterotoxigenic B. fragilis causes colonic signal
transduction and activates transcription-3 (Stat3)
activation and T helper 17 (Th17) cell responses,
thereby promoting colon tumorigenesis.117
Patients with colorectal cancer have been found
to have more B. fragilis than healthy controls.
Furthermore, F. nucleatum, which is more preva­
lent in the feces of people with CRC, is known to
adhere to colorectal cancer cells. This bacterium
might aid cancer growth by promoting inflamma­
tion and inhibiting the immune response.118,119 In
particular, the F. nucleatum can stimulate TLR4
signaling to encourage the development of
tumors.67,120 Extracellular superoxide and hydro­
gen peroxide produced by E. faecalis have been
shown to cause DNA damage in colonic epithelial
cells.67 Additionally, E. faecalis can produce cyto­
toxic necrotizing factor 1 (CNF1), which results in
the growth and spread of cancer cells.120
Additionally, E. coli and Streptococcus gallolyticus
both promote CRC development.68,69 Polyketide
synthase-positive (pks+) E. coli-derived colibactin,
a small-molecule genotoxin, can induce doublestrand DNA breaks (DSBs), causing DNA damage
in colonic epithelial cells to facilitate CRC
progression.121,122 In addition to these bacterial
species that promote colorectal cancer, the intest­
inal microbial community structure of colorectal
cancer patients also has unique characteristics that
are significantly different from those of healthy
people. Human studies have revealed that CRC
patients have increased species richness in the gut
microbiota, with decreases in Roseburia and
increases in the Bacteroides, Escherichia,
Fusobacterium, and Porphyromonas genera.64,65
Another study demonstrated that the genera
Prevotella, Peptostreptococcus, Parvimonas and
GUT MICROBES
5
Table 1. Characteristics of the Gut Microbiota in Patients with Various Types of Cancer.
Cancer type
Gastric cancer
Gut microbiome
Patients with gastric cancer had six times the amount of H. pylori in their feces as people without the disease.
Clostridium XVIII, Veillonella, and Escherichia/Shigella were more prevalent, with the abundance of Bacteroides
decreasing in the gastric cancer group.
Escherichia, Lactobacillus, and Klebsiella were increased in the fecal samples.
The relative abundance of Veillonella, Megasphaera, and Prevotella increased at the genus level. Lactobacillus
salivarius, Streptococcus salivarius, and Bifidobacterium dentium increased at the species level.
The proportion of probiotic Bifidobacterium was decreased, while the pathogens Streptococcus,
Peptostreptococcus, and Prevotella were raised in the gut microbiota.
Bacteria from the Enterobacteriaceae family are more prevalent, whereas those from the Lactobacillaceae
family are less prevalent.
Colorectal cancer
Decrease the abundance in Roseburia and increase in Bacteroides, Escherichia, Fusobacterium, and
Porphyromonas genera.
B. fragilis, E. coli, F. nucleatum, S. gallolyticus, and E. faecalis were found to have higher abundance.
Increasingly more fecal samples contained members of the genera Prevotella, Peptostreptococcus, Parvimonas,
and Porphyromonas.
C. difficile was also enriched in CRC patients.
As potential CRC pathogens, E. coli, F. nucleatum, enterotoxigenic B. fragilis, Streptococcus bovis,
Peptostreptococcus anaerobius, and E. faecalis have all been observed.
Genera Bacteroides, Enterococcus, Escherichia, and Clostridium could contribute to CRC development.
Esophageal cancer
Patients with esophageal cancer had more Firmicutes and Actinobacteria, with a decline in Bacteroidetes.
There are fewer Spirochaetes, Fusobacteria, and Bacteroidetes in the patient’s fecal samples.
Hepatocellular carcinoma
The abundance of Streptococcus, Prevotella_9, Faecalibacterium, and Bacteroides was increased.
(HCC)
In fecal samples of HCC patients, the genera Lactobacillus and Streptococcus were enriched, whereas the
Akkermansia, Subdoligranulum, Prevotella_2, and Faecalibacterium were reduced.
Ruminococcaceae, Porphyromonadaceae, and Bacteroidetes were decreased.
In fecal samples of liver cancer patients, lipopolysaccharide (LPS)-producing genera, such as Klebsiella,
increased, whereas butyrate-producing genera, such as Ruminococcus, decreased.
The presence of GelE-positive E. faecalis can promote the process of liver cancer.
Intrahepatic
Lactobacillus, Alloscardovia, Peptostreptococcaceae, and Actinomyces were enriched in ICC patients.
cholangiocarcinoma (ICC) Ruminococcaceae, Porphyromonadaceae, and Bacteroidetes were decreased in patients with intrahepatic
cholangiocarcinoma.
Lactobacillus, Actinomyces, Peptostreptococcaceae, Alloscardovia, and Bifidobacteriaceae were higher in the
fecal samples of patients.
Cholangiocarcinoma (CCA) The genera Bacteroides, Alistipes, Muribaculaceae unclassified, and Muribaculum were particularly abundant in
the CCA patients.
Patients had considerably higher Bacteroides, Anoxybacillus, Meiothermus, and Geobacillus levels than controls.
Pancreatic ductal
Proteobacteria, Fusobacteria, Actinobacteria, and Verrucomicrobia were more prevalent in PDA patients’ guts.
adenocarcinoma (PDA)
Patients with PDA had enriched gut populations of Bacteroidetes Firmicutes, Actinobacteria, and
Proteobacteria, as well as the genera that make up these four phyla.
Proteobacteria, Euryarchaeota, and Synergistetes were substantially more prevalent in PDA patients.
Romboutsia timonensis, F. prausnitzii, Bacteroides coprocola, and Bifidobacterium bifidum were depleted, while
Fusobacterium hwasookii, F. nucleatum, V. atypica, and A. omnicolens were enriched in the feces of patients
with pancreatic adenocarcinoma.
Patients with pancreatic adenocarcinoma had higher concentrations of the bacteria V. parvula, Streptococcus
species, and V. atypica and lower concentrations of F. prausnitzii.
Breast Cancer (BC)
The increase of Blautia sp. was associated with the stage of breast tumor development.
Lactobacilli, Enterobacteriaceae, and aerobic Streptococci were higher in premenopausal BC patients’ feces.
In comparison to healthy women, premenopausal breast cancer patients exhibited a noticeable rise in the
presence of Bacteroides, Clostridia, and aerobic Lactobacilli.
Eubacterium eligens and Roseburia inulinivorans decreased, while increased abundances of Enterococcus
gallinarum, Erwinia amylovora, E. coli, Citrobacter koseri, Acinetobacter radioresistens, Actinomyces spp.
HPA0247, Shewanella putrefaciens, Salmonella enterica, and F. nucleatum were observed in postmenopausal
BC patients.
Patients with postmenopausal BC showed elevated levels of Ruminococcaceae, Clostridiaceae, and
Faecalibacterium and low amounts of Dorea and Lachnospiraceae.
Patients with postmenopausal BC had higher levels of Clostridiales, and the abundance of Bacteroides
decreased in their feces.
Lymphoma
Lactobacillus johnsonii was lacking in lymphoma mice.
Lung cancer
Enterococcus was enriched in the gut microbiota of lung cancer patients.
Dialister, Kluyvera, Faecalibacterium, Escherichia-Shigella, and Enterobacter were decreased, whereas
Bacteroides, Fusobacterium, and Veillonella were notably higher in lung cancer patients.
Bacillus and Akkermansia muciniphila were enriched and facilitated the growth of lung cancer.
Eight genera, including Collinsella, Klebsiella, Enterococcus, Bifidobacterium, Lactobacillus, Streptococcus,
Escherichia, and Dorea, were increased in the feces of lung cancer patients, yet Prevotella and Coprococcus
abundances had a sharp decline.
At the genus level, three genera, Bacteroides, Fusobacterium, and Veillonella, were higher, while five genera,
Escherichia-Shigella, Dialister, Kluyvera, Enterobacter, and Fecalibacterium were decreased in the lung cancer
patients.
Non-small cell lung cancer Rikenellaceae, Enterobacteriaceae, Prevotella, Lactobacillus, Streptococcus, Oscillospira, and Bacteroides plebeius
were significantly higher in the NSCLC patients.
Gut butyrate-producing bacteria exhibited remarkably low levels, including Clostridium leptum, Clostridial
Cluster I spp, Ruminococcus, and F. prausnitzii.
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(Continued)
6
S. JIANG ET AL.
Table 1. (Continued).
Cancer type
Gut microbiome
Prostate cancer
The abundance of Bacteroides massiliensis increased, while Eubacterium rectalie and F. prausnitzii levels
decreased in the gut of people with prostate cancer.
Cancer patients had an enrichment in genera Fusobacterium, Actinobaculum, Facklamia, Campylobacter,
Veillonella, and Streptococcus, while Corynebacterium was decreased in the gut.
Thermoactinomycetaceae was enriched, and the abundance of Sphingobacteriaceae was significantly
decreased in cancer patients.
Prevotella and Clostridium cluster XI were decreased in the gut.
The beneficial bacteria Actinobacteria, Coprococcus, Bifidobacterium, and Ruminococcus were decreased, while
Bacteroides, Peptostreptococcus, Proteobacteria, Fusobacteria, Prevotella, and Gardnerella were observed to
had significant enrichment of in epithelial ovarian cancer patients.
The genus Akkermansia was markedly reduced.
In the intestines of patients with early-stage cervical cancer, there is a decrease in Bacteroides, Bifidobacterium,
Haemophilus, Faecalibacterium, Blautia, Clostridium, Roseburia, Ruminococcus, Gemmiger, Lachnospira,
Unclassified Lachnospiraceae, and Unclassified Clostridiales, and a stimulation of various other genera
including Prevotella, Streptococcus, Varibaculum, Peptoniphilus, Actinobaculum, Finegoldia, Dialister,
WAL_1855D, Peptostreptococcus, Anaerococcus, and Corynebacterium.
There were increases in the phylum Proteobacteria and genera Parabacteroides, Escherichia Shigells, and
Roseburia.
Bladder cancer
Epithelial ovarian cancer
(EOC)
Cervical cancer
Porphyromonas were increased in the fecal samples
of
CRC
patients.71–74
Among
them,
Peptostreptococcus anaerobius, which belongs to
the genus Peptostreptococcus, is a CRC-enriched
bacterium that promoted carcinogenesis by activat­
ing the TLR2 and/or TLR4 pathways in mouse
models.123 Moreover, Clostridium difficile was
also enriched in CRC patients.75
These unique characteristics can be used as bio­
markers for early diagnosis. Yu and her team
employed seven bacterial species, including
B. fragilis, F. nucleatum, Parvimonas micra,
Porphyromonas asaccharolytica, Prevotella inter­
media, Thermanaerovibrio acidaminovorans, and
Alistipes finegoldii, as biomarkers for early-stage
colorectal cancer diagnosis. They achieved an area
under the receiver-operating characteristics curve
(AUC) of 0.80; when combined with clinical infor­
mation, the accuracy was further enhanced to an
AUC of 0.88.124 Additionally, Ma et al. developed
an innovative prediction model that utilized single
nucleotide variant (SNV) sites within the gut
microbiota to diagnose early CRC. This prediction
model contained 22 single-nucleotide variant sites
(SNVs), primarily derived from Eubacterium rec­
tale and F. nucleatum, and the model demonstrated
high accuracy in distinguishing between disease
and healthy cohorts (AUC = 73.08%~88.02%).
Furthermore, when tested via a meta-analysis that
included patients with other metabolic disorders,
the model exhibited excellent specificity.23,125
Esophageal cancer has long been regarded as one
of the most prevalent cancers in the world, with
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common symptoms including difficulty swallow­
ing, which can lead to indigestion.126 Park et al.
shed light on a potential link between gramnegative bacteria expressing lipopolysaccharides
and enhanced inducible nitric oxide synthase
expression (iNOS). This may lead to a reduction
in esophageal sphincter relaxation, which ulti­
mately contributes to gastroesophageal reflux dis­
ease (GERD) and is linked to an increased risk of
esophageal cancer.127 In the context of esophageal
cancer, distinct alterations in the gut microbiota
have been observed. Compared to healthy indivi­
duals, patients with esophageal cancer often have
lower levels of Bacteroidetes and higher amounts of
Firmicutes and Actinobacteria.77 Other research
has also shown that individuals with esophageal
cancer have lower Bacteroidetes, Fusobacteria,
and Spirochaetes in their feces.78
Amino acids, bile acids, short-chain fatty acids,
and choline are essential signaling molecules and
metabolic substrates that influence liver
function.128,129 Intestinal barrier dysfunction
allows intestinal-derived bacteria and microbiota
metabolites, particularly lipopolysaccharides, to
induce CXCL1 expression in hepatocytes in
a TLR4-dependent manner and increase CXCR2+
PMN-MDSCs. The increase in PMN-MDSCs could
induce liver cells to form an immunosuppressive
environment and lead to the occurrence of liver
cancer.130 In fecal samples of hepatocellular carci­
noma (HCC) patients, the genera Streptococcus,
Lactobacillus Prevotella_9, Faecalibacterium, and
Bacteroides were enriched, whereas Akkermansia,
GUT MICROBES
7
Table 2. Characteristics of the microbiomes in various types of Tumors.
Cancer type
Intramucosal carcinomas
CRC
Lung cancer
Pancreatic cancer
Melanoma
Esophageal cancer
Liver cancer
Intratumoural microbiome
Atopobium parvulum and Actinomyces odontolyticus abundance dramatically increased at an early stage of
multiple polypoid adenomas and intramucosal carcinomas. Moreover, the number of F. nucleatum continues
to rise into the late stages of cancer.
From the early to the late stages of carcinogenesis, the species Solobacterium moorei and F. nucleatum showed a
considerable increase in abundance.
Enterotoxigenic B. fragilis (ETBF) has a high abundance in tumors.
Colonizing tumors by pks+ E. coli leads to an increase in tumor multiplicity and invasion.
F. nucleatum was observed to have a significant concentration in CRC cancerous tissue.
The abundance of phyla Firmicutes and Bacteroidetes were dominant in colorectal tumors.
High levels of Haemophilus influenzae, E. coli, Staphylococcus, and Enterobacter were shown in lung cancer
tissues.
Significant alterations in Neisseria, Capnocytophaga, and Veillonella were confirmed among lung cancer patients.
Streptococcus, Acinetobacter, Thermus, Megasphaera, Granulicatella adiacens, Enterococcus, Prevotella, Rothia,
Brevundimonas, Propionibacterium, Enterobacter, E. coli and Legionella were identified in tumor tissues.
Acidovorax is more prevalent in the tissue of squamous cell carcinoma.
The Actinobacteria and Firmicutes phyla were enriched in the lung cancer tissue.
Phyla such as Firmicutes and TM7, as well as genera Veillonella and Megasphaera, were notably elevated in lung
cancer tissues.
Genera Klebsiella, Comamonas, Rhodoferax, Acidovorax, and Polarmonasare were more commonly discovered in
SCC.
The genera Staphylococcus, Escherichia, and Bacillus were the characteristic markers of the lung cancer group.
Thermus genus abundance was increased and related to advanced-stage cancer.
Pseudoxanthomonas, Streptomyces spp., and Saccharopolyspora were enriched in patients with longer survival
rates. Meanwhile, Bacillus clausii increased in pancreatic adenocarcinoma (PDAC) patients with shorter
survival.
Proteobacteria dominated the microbiome of pancreatic adenocarcinoma.
F. nucleatum enriched in PDAC cohorts.
Gammaproteobacteria were detected in 76% of PDAC patients.
Proteobacteria (45%), Bacteroidetes (31%), Firmicutes (22%), and Actinobacteria (1%) were most prevalent in
human pancreatic ductal adenocarcinoma (PDA) samples. At the genus level, the genera Pseudomonas and
Elizabethkingia were predominant in PDA samples.
B. pseudolongum was detected in the pancreas.
Fusobacterium and Trueperella were enriched in melanoma tumors.
In tumors of anti-PD-1 immunotherapy responders, Clostridium was more predominant, while Gardnerella
vaginalis was enriched in nonresponders’ tumors.
F. nucleatum in esophageal cancer tissues promoted aggressive tumor behaviors and was correlated with a poor
prognosis.
Bacteroides and Bifidobacterium were detected in the tumor lesion, which was linked to hepatocellular
carcinoma caused by HBV.
The phyla Proteobacteria and Actinobacteria were dominant in the TME of HCC.
Pseudomonadaceae was decreased, while the family Rhizobiaceae and genus Agrobacterium were markedly
elevated in tumor tissues, which had a linear relationship with patients’ chances of surviving primary liver
cancer.
Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes were the most prevalent bacterial phyla in
malignancies.
A total of 266 species, including those of Burkholderiales, Pseudomonadales, Xanthomonadales, Bacillales,
Clostridiales, and Sphingomonadales, were detected in intrahepatic cholangiocarcinoma.
Intrahepatic
cholangiocarcinoma
(ICC)
Cholangiocarcinoma (CCA) There was an increase in three Helicobacter species, H. Pylori, H. Bilis, and H. Hepaticus.
Breast cancer (BC)
B. fragilis was detected in cancerous breast tissues.
A high accumulation of the genera Fusobacterium was observed in the microbiome of malignant breast tissue
samples.
F. nucleatum is enriched and accelerates the development and metastasis of breast tumors.
Comamondaceae, Bacteroidetes, Enterobacteriaceae, Bacillus, and Staphylococcus were enriched in BC cancer
patients.
The genus Propionicimonas, family Methylobacteriaceae, Caulobacteraceae, Nocardioidaceae,
Rhodobacteraceae, and Micrococcaceae were enriched in BC tissues.
The genus Agrococcus, which is connected to the emergence of malignancy, and the relative abundance of the
family Bacteroidaceae was reduced.
Firmicutes, Actinobacteria, and Proteobacteria, were increased, and the species Mycobacterium phlei and
Mycobacterium fortuitum were also abundant in breast tissues.
In the four BC subtypes, Proteobacteria and Actinomyces were also confirmed to be significant enrichment.
Actinobacteria, Proteobacteria, Bacteroidetes, Firmicutes, and Verrucomicrobia were enriched in breast tissue.
Methylobacterium radiotolerans was enriched, while Sphingomonas yanoikuyae decreased in breast tumor tissue
at the genus level.
Gastric cancer
Persistent infection with H. pylori has been determined to be a significant factor in the progression of gastric
cancer.
Esophageal cancer
Intratumoural F. nucleatum was detected and could affect the malignant behavior of esophageal cancer.
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(Continued)
8
S. JIANG ET AL.
Table 2. (Continued).
Cancer type
Prostate cancer
Oral squamous cell
carcinoma (OSCC)
Intratumoural microbiome
Staphylococcus saprophyticus and Vibrio parahaemolyticus were significantly decreased, and Shewanella and
Microbacterium were enriched.
The most common bacteria were Propionibacterium acnes spp., which were strongly related to prostate tissue
inflammation.
Family Enterobacteriaceae, specifically the genera Escherichia and Propionibacterium acnes, were dominant in
tumors, with a relative abundance of 95%.
Staphylococcus spp exhibited an increased abundance in tumors.
More than 40 distinct bacterial genera were identified and dominant in the tumors, including Pseudomonas,
Escherichia, Acinetobacter, and Propionibacterium.
The phyla Actinobacteria, Firmicutes, Proteobacteria, and Bacteroidetes were predominant in tumors.
The genus Peptostreptococcus was detected, and higher levels of Peptostreptococcus were correlated with longterm survival.
The intratumoral microbiota was dominated by bacterial species that belong to the Fusobacterium and
Treponema genera.
References
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195
196
197
198
199
Figure 2. The crosstalk between gut microbiome and TME.
Subdoligranulum,
Prevotella_2,
and
Faecalibacterium were reduced. These bacteria are
all involved in BA synthesis.79–82,131 Meanwhile, in
fecal samples of liver cancer patients, lipopolysac­
charide (LPS)-producing genera, such as Klebsiella,
increased, whereas butyrate-producing genera,
such as Ruminococcus, decreased.84 Research has
shown that the presence of GelE-positive E. faecalis
can promote the progression of liver cancer. This
bacterium expressed metallopeptidase GLE, which
increased intestinal permeability, led to an increase
in plasma lipopolysaccharides and activation of
GUT MICROBES
hepatocyte TLR4-MYD88 proliferation signaling,
and finally promoted the development of liver
cancer.85
Based on these microbes, eight genera, including
Faecalibacterium,
Lactobacillus,
Klebsiella,
Citrobacter, Dorea, Ruminococcus Gnavus group,
Veillonella, and Burkholderia Caballeronia
Paraburkholderia, were proposed to be used in
the gut microbiota-based model, and high accuracy
(AUC >0.90) was obtained when distinguishing
patients with liver cancer from healthy
controls.132 Zhang et al. employed only the three
genera mentioned above, Faecalibacterium,
Burkholderia Caballeronia Paraburkholderia, and
Ruminococcus-1, as biomarkers to differentiate
between cholangiocarcinoma (CCA) patients and
healthy subjects.88 Han et al. employed
Enterococcus, Lactobacillus, and Escherichia as bio­
markers to distinguish between groups with and
without lung cancer and achieved an accuracy of
0.81.103
Chronic inflammation is intimately related to
cancer development, and the gut microbiome may
impact pancreatic tissue through the inflammatory
process, thereby promoting the growth and spread
of pancreatic cancer. In patients with pancreatic
ductal adenocarcinoma (PDA), comparative inves­
tigations of the gut microbiota have revealed that at
the phylum level, Proteobacteria, Actinobacteria,
Fusobacteria, and Verrucomicrobia are more pre­
valent in these patients’ guts.90 During the inflam­
matory process, changes in gut permeability occur,
which enable the translocation of intestinal micro­
organisms, particularly those belonging to the
Proteobacteria phylum, which migrate to the pan­
creas and accumulate there. In turn, Toll-like
receptor 2 and Toll-like receptor 5 are conse­
quently activated in the pancreas and trigger down­
stream immune suppression. This combined effect
and genetic risk factors promote the development
of PDA.90,133 Additionally, another study indicated
that pancreatic adenocarcinoma patient feces con­
tained higher concentrations of the bacteria
Fusobacterium hwasookii, Veillonella atypica,
F. nucleatum, and Alloscardovia omnicolens. At
the
same
time,
Bacteroides
coprocola,
Faecalibacterium prausnitzii, Romboutsia timonen­
sis, and Bifidobacterium bifidum were deficient.91
Similarly, another pancreatic adenocarcinoma
9
patient study confirmed a decrease in
F. prausnitzii. Concurrently, Veillonella parvula,
V. atypica, and Streptococcus species were more
abundant in the intestines.92
Breast cancer predominantly affects females,
with a significant increase in breast cancer risk
observed during menopause. Hormone levels
undergo substantial fluctuations in women before
and after menopause, accompanied by significant
alterations in the gut microbiota. Consequently,
compared to healthy individuals, there are distinct
characteristics in the gut microbiota of premeno­
pausal and postmenopausal breast cancer patients.
In premenopausal breast cancer patients, more
Enterobacteriaceae, Lactobacilli, and aerobic
Streptococci were present compared to healthy
individuals.94 Additionally, there was an observable
increase in the presence of Bacteroides, Clostridia,
and aerobic Lactobacilli.95 However, postmenopau­
sal breast cancer patients had a decrease in
Bacteroides abundance and an increase in
Clostridiales abundance.98 At the species level, post­
menopausal breast cancer patients exhibited
a decreased abundance of Roseburia inulinivorans
and Eubacterium eligens, while Acinetobacter radio­
resistens, E. coli, Salmonella enterica, Erwinia amy­
lovora, Citrobacter koseri, Shewanella putrefaciens,
Enterococcus gallinarum, Actinomyces spp.
HPA0247 and F. nucleatum had an increased
abundance.96 The reason behind these differences
is widely believed to be linked to fluctuations in
estrogen levels, which have been linked to the devel­
opment of breast cancer. Possible mechanisms
include, on the one hand, the hypothesis that estro­
gen metabolism can be influenced by gut bacteria.
For postmenopausal women in particular, elevated
estrogen levels are a significant risk factor for breast
cancer.134 Certain gut microbiota can also induce
16α-hydroxylation of estrogen, which raises the risk
of developing breast cancer.135 On the other hand,
a high-fat diet may cause the gut microbiota of
patients to create steroidal chemicals that are linked
to cancers. These steroids may influence estrogen
levels or affect breast tissue, which could promote
the growth of tumors.136 Furthermore, breast can­
cer incidence and inflammation are tightly related.
The gut microbiota regulates mucosal and systemic
immune responses, impacting cancer cells and the
surrounding environment.137 This influences
10
S. JIANG ET AL.
obesity status, breast cancer risk, and endogenous
and exogenous metabolism.138
These findings highlight the intricate interplay
between specific gut microbiomes and the devel­
opment of colorectal cancer, thereby offering
potential avenues for further research and thera­
peutic interventions.
3.2. The gut microbiome and the tumor
microenvironment (TME)
Although the gut microbiota has been identified as
a pivotal biomarker and modulator in cancer devel­
opment and treatment response, recent research
has provided evidence that the gut microbiota has
a crucial impact on the TME and impacts both
local and distant tumors (Figure 2). One notable
example is pancreatic adenocarcinoma, a cancer
typically associated with poor survival rates.
Research conducted in 2019 on pancreatic adeno­
carcinoma patients revealed that long-term respon­
ders, specifically those surviving for over five years,
exhibited a more diverse tumor microbiome than
short-term survivors. Notably, some of the
microbes within the tumors originated from the
gut, which may communicate through the pancrea­
tic duct and may be impacted by the regulation of
gut microbial communities.139 This underscores
the role of gut microbiota in the tumor microen­
vironment, a role further supported by experi­
ments involving fecal microbiota transplantation
(FMT). FMT from long-term survivors effectively
slowed tumor development in pancreatic adeno­
carcinoma mice and bolstered their immune cell
activity.140 Many studies have also reinforced the
importance of local microbial communities as
essential constituents of the TME. This significance
is particularly evident in cancers developing at
mucosal locations such as the lungs, skin, and
gastrointestinal tract.141–144 Notably, the bacterial
populations residing in tumors are unique to cer­
tain tumors.145,146
3.2.1. Characteristics of the tumor microbiome in
various types of tumors
Microbiomes are present in various tumor tissues
and play a vital role in tumor development, metas­
tasis, and treatment. Within the context of cancer
development, microbes within the tumor
microenvironment can be a double-edged sword.
On the one hand, they can facilitate tumor devel­
opment and spread through mechanisms such as
inducing DNA mutations, activating oncogenic
pathways, fostering chronic inflammation, and
promoting complement system activity and
metastasis.147 On the other hand, these tumorassociated microbes may also contribute to inhibit­
ing tumor growth or enhancing the immune sys­
tem’s response. They can either strengthen or
weaken the antitumor immune response, induce
different immunotherapeutic effects and outcomes,
and impact long-term survival rates.147,148 Notably,
recent research by Nejman et al. analyzed seven
different cancer types and revealed distinct micro­
bial compositions within tumors and cells across
various cancer types.148 Numerous studies have
also found that different tumor types exhibit
unique microbial community structures in tumors
such as those associated with colorectal, lung, and
breast (Table 2).148–150
The phyla Firmicutes and Bacteroidetes were the
most predominant in colorectal cancer tissues.148
Yachida et al. found that the species F. nucleatum
and Solobacterium moorei showed a progressive
rise from the early to late stages of carcinogenesis
in colorectal tumors.72,151 In addition, enterotoxi­
genic B. fragilis and E. coli both had a high abun­
dance of tumors, and the colonization of tumors by
E. coli expressing the genomic island polyketide
synthase (pks+ E. coli) leads to an increase in
tumor multiplicity and invasion.68,152–154
Lung cancer is the most prevalent cancer, with
the highest occurrence and fatality rates. Research
has shown that both healthy and diseased lungs are
not sterile environments. Tumor tissues harbor
unique microbial communities. For instance,
Laroumagne et al. detected E. coli, Haemophilus
influenzae, Enterobacter, and Staphylococcus
enrichment in lung cancer tissues.155 Lee et al.
identified phyla such as Firmicutes and TM7 and
genera including Veillonella and Megasphaera that
were notably elevated in lung cancer tissues.156
Another study revealed specific microbial compo­
sitions in lung cancer tumor tissues, including
Streptococcus,
Acinetobacter,
Thermus,
Megasphaera,
Granulicatella
adiacens,
Enterococcus, Prevotella, Rothia, Brevundimonas,
Propionibacterium, Enterobacter, E. coli and
GUT MICROBES
Legionella.157–159 Research has indicated that the
Actinobacteria and Firmicutes phyla showed
a higher abundance in lung cancer tissues than in
healthy individuals.160 The genera Staphylococcus,
Escherichia, and Bacillus were the characteristic
markers of the lung cancer group.161
Discrepancies in detection results may be attribu­
ted to tumor subtypes, sampling locations, differ­
ent stages of the disease, and various detection
methods. Yu et al. found that the abundance of
the Thermus genus was increased and related to
advanced-stage cancer.143 Yan et al., using quanti­
tative PCR methods, confirmed the significant
alterations in Neisseria, Capnocytophaga, and
11
Veillonella among lung cancer patients.156,162,163
In addition, in small-cell carcinoma (SCC), the
genera Klebsiella, Comamonas, Rhodoferax,
Acidovorax, and Polaromonas are commonly
reported.164
In pancreatic ductal adenocarcinoma, at the
phylum level, the bacterial phyla Proteobacteria
(45%), Bacteroidetes (31%), Firmicutes (22%),
and Actinobacteria (1%) were most prevalent in
human pancreatic ductal adenocarcinoma (PDA)
samples. Proteobacteria dominate the microbiome
of pancreatic adenocarcinoma,90 and these bacteria
can induce T-cell anergy in a Toll-like receptordependent manner, thereby hastening the
Figure 3. Cancer Immunotherapy Strategies included immunotherapy checkpoint inhibitors, adoptive cellular therapy, cancer
vaccines, and cytokine therapy.
12
S. JIANG ET AL.
advancement of tumors. Among them,
Gammaproteobacteria were detected in 76% of
PDAC patients.165 At the genus level, the genera
Pseudomonas and Elizabethkingia were predomi­
nant in human PDA samples.90 Bifidobacterium
pseudolongum was also detected in the pancreas.90
Additionally, another study indicated that
F. nucleatum was enriched in PDAC cohorts.148
Riquelme et al. found that Pseudoxanthomonas,
Streptomyces spp., and Saccharopolyspora were
enriched in patients with longer survival rates. In
contrast, Bacillus clausii was increased in pancrea­
tic adenocarcinoma (PDAC) patients with shorter
survival.140
In cholangiocarcinoma tumors, a total of 266
species, including those of Clostridiales,
Sphingomonadales,
Pseudomonadales,
Burkholderiales, Bacillales, and Xanthomonadales,
were
detected
in
intrahepatic
cholangiocarcinoma.166 There was also an increase
in H. pylori, Helicobacter hepaticus, and
Helicobacter bilis.167,168 The potential mechanism
underlying these changes is that gram-negative
bacteria
affect
hepatocytes
to
create
a microenvironment that is immunosuppressive
by inducing CXCR2+ PMN-MDSC accumulation
through TLR4-dependent CXCL1 production,
thereby promoting the development of liver
tumors.169
Breast cancer (BC) is one of the most prevalent
malignancies in women. Numerous studies have
identified microorganisms important for breast
tumor development, progression, and prognosis.
Actinobacteria, Proteobacteria, Bacteroidetes,
Firmicutes, and Verrucomicrobia were enriched
in breast tumor tissues.170 Thompson et al. also
confirmed that Firmicutes, Actinobacteria, and
Proteobacteria were increased, and the species
Mycobacterium phlei and Mycobacterium fortuitum
were abundant in breast tissues as well.171 In the
four BC subtypes, Proteobacteria and Actinomyces
were also confirmed to be significantly enriched.172
According to Xuan et al., Methylobacterium radio­
tolerans was enriched, while Sphingomonas yanoi­
kuyae was decreased in breast tumor tissue at the
genus level.170 Many studies have found that
F. nucleatum is enriched and accelerates the devel­
opment and metastasis of breast tumors.148,173,174
In malignant breast tissue samples, the genus
Fusobacterium was found to have a high
accumulation.174 F. nucleatum can promote
aggressive tumor behaviors through Treg lympho­
cytes in a chemokine-dependent manner, particu­
larly involving CCL20; this bacterium is thereby
associated with an unfavorable prognosis.175
B. fragilis was also detected in cancerous breast
tissues.176 Urbaniak et al. indicated that
Comamondaceae,
Bacteroidetes,
Enterobacteriaceae, Bacillus, and Staphylococcus
were enriched in BC cancer patients.177 Meng
et al. showed that the genus Propionicimonas and
families Methylobacteriaceae, Caulobacteraceae,
Nocardioidaceae,
Rhodobacteraceae,
and
Micrococcaceae were enriched in BC tissues.178
Additionally, the genus Agrococcus, which is con­
nected to malignancy, and the relative abundance
of the family Bacteroidaceae were reduced.178
3.2.2. The tumor microbiome and tumor
development
The tumor microbiome, which accounts for
approximately 25% of all cells in the tumor envir­
onment (including immune cells, cancerassociated fibroblasts, endothelial cells, pericytes,
etc.), influences tumor development and treatment
through various mechanisms.200 These mechan­
isms include inducing DNA damage and muta­
tions, thereby directly promoting tumorigenesis
by increasing mutagenesis,145,201,202 activating
oncogenic signaling pathways, and enhancing cell
proliferation and transformation.203,204 Several stu­
dies have pointed to members of the
Enterobacteriaceae family, which produce colibac­
tin, a DNA-damaging toxin that induces senes­
cence in epithelial cells. Senescent cells activate
signaling pathways that ultimately promote the
proliferation of neighboring cells unaffected by
colibactin damage, thus inducing tumor
formation.205 The pks+ E. coli, a bacterium
known to cause DNA damage, leads to distinct
mutational features in organoids.206 Another
group of bacteria capable of inflicting DNA
damage includes enterotoxigenic B. fragilis, which
produces a toxin called fragilysin. This zincdependent metalloproteinase promotes the clea­
vage of epithelial cell E-cadherin. This cleavage
releases β-catenin, activating cell proliferationregulating transcription factors and facilitating the
GUT MICROBES
proliferation of colon epithelial cells.207
Furthermore, F. nucleatum, with its antigen adhe­
sin A (FadA), encourages the development of CRC
through the E-cadherin-calcium-catenin-Wnt-βcatenin signaling pathway.208 H. pylori contributes
to CRC through the induction of inflammation and
by regulating mucosal cell growth and proliferation
via critical intracellular signaling pathways.209
Additionally, the tumor microbiome can also
break down and metabolize antitumor drugs, redu­
cing their effectiveness and leading to drug
resistance.210 For instance, Ravid Straussman’s
research has demonstrated that microbes within
tumors can directly metabolize gemcitabine, lead­
ing to chemotherapy resistance in pancreatic can­
cer. Gemcitabine resistance was mediated by
intratumoral
Gammaproteobacteria
and
Bifidobacterium pseudolongum in mouse
models.165,211 Moreover, certain bacteria, including
intratumoral Mycoplasma hyorhinis and species of
Proteobacteria, can also metabolize gemcitabine
into 2,2-difluoro deoxyuridine, rendering the
drug inactive and causing resistance.165 Using
ciprofloxacin to eliminate bacteria could overcome
this resistance in mouse models.
The tumor microbiome can also modulate the
host immune system, thereby influencing
immune cell activation and polarization and
altering the immune milieu within the tumor
microenvironment.212 For instance, intratumoral
bacteria can activate the functionality of antitu­
mor T cells by producing immunogenic mole­
cules or stimulating interferon signaling.213
Certain intratumoral microbes can affect the
synthesis and secretion of cytokines such as IL6 and TNF-α.214 Numerous studies indicate that
the intratumoral microbiota may impact cyto­
kine production, thereby inducing proinflamma­
tory responses that subsequently activate the
NF-κB or STAT3 pathway to promote tumor
development.215,216 Triner and colleagues
showed that intratumoral bacteria induce the
production of IL-17, which promotes B-cell
infiltration
and
tumor
development.217
Additionally, Toll-like receptors, including
TLR4 and TLR5, are closely connected to the
interactions between tumors and microorgan­
isms (including the gut and intratumoral
microbiota).218
13
4. The gut microbiome and tumor
immunotherapy
4.1. Cancer immunotherapy strategies
Tumor immunotherapy is an approach to treat­
ment that stimulates the body’s tumor-specific
immune responses, either actively or passively, to
harness their inhibitory and cytotoxic functions
against cancer cells.4 It offers advantages such as
specificity, efficiency, and minimal harm to healthy
tissues. Unlike conventional treatments such as
surgery, targeted therapy, and chemotherapy,
immunotherapy does not directly kill cancer
cells.219 Instead, it mobilizes immune cells within
the body capable of recognizing tumors, enhances
the body’s immune system’s capabilities, and relies
on them to indirectly eliminate and control
cancer.220 This method has fewer side effects, mak­
ing it a safe and effective alternative.
Immunotherapy encompasses various approaches,
including immunotherapy checkpoint inhibitors,
adoptive cellular therapy (CAR-T, TIL, NK, and
CIK/DC-CIK), cancer vaccines, molecular targeted
therapies, and immunomodulators such as cyto­
kine therapy (Figure 3).4
Immunotherapy checkpoint inhibitors (ICIs) act
based on the following principles: Immune check­
point molecules are crucial for regulating the onset
and magnitude of immune responses, preserving
self-tolerance and autoimmune responses, and
reducing tissue damage.221 These checkpoints are
expressed on immune cells and inhibit their func­
tions, thereby preventing an effective antitumor
immune response and allowing tumors to evade
the immune system.222 Key immune checkpoint
molecules associated with cancer are PD-1, Tim3, CTLA-4, and LAG-3, with the most extensively
researched checkpoint inhibitors being PD-1/PDL1 and CTLA-4 inhibitors.4 Their primary func­
tion is to impede the interaction between tumor
cells expressing immune checkpoints and immune
cells, thus thwarting the inhibitory impact of tumor
cells on immune cells.
Adoptive cellular immunotherapy (ACI) acts via
the following mechanisms: Adoptive cellular
immunotherapy transfers immune cells possessing
antitumor activity, encompassing specific and non­
specific responses, into individuals with cancer.
Immune cells can directly eliminate or trigger the
14
S. JIANG ET AL.
body’s immune response to eradicate tumor
cells.223 Cell-based immunotherapy has always
been one of the most active areas in cancer biother­
apy. This therapy is particularly suitable for
patients with compromised immune function,
leading to reduced immune cell numbers and
impaired function, especially for patients with
hematological or immunological malignancies. (1)
Chimeric antigen receptor T-cell (CAR-T) therapy
involves extracting immune lymphocytes from the
patient’s blood and genetically engineering them.
This modification allows T cells to recognize tumor
cell antigens while enhancing their antitumor
activity. Then, the modified T cells are reintro­
duced into the host, specifically targeting and kill­
ing cancer cells.224 (2) Tumor-infiltrating
lymphocyte (TIL) therapy involves isolating lym­
phocytes infiltrating tumor tissue and selecting
those with specific anticancer properties.225 After
activation and expansion, these selected lympho­
cytes are reintroduced into the patient’s body to
recognize and target tumor cells specifically. TILs
consist of T cells that directly infiltrate tumor tis­
sue, which makes them suitable for solid tumors.
(3) Natural killer (NK) cell therapy is based on the
following principles: NK cells function as the
body’s initial line of defense against cancer and
infections and have stronger and more efficient
capabilities in killing tumor and virus-infected
cells than other immune cells.226 By isolating and
expanding from tumor tissue and then reintrodu­
cing them into the patient’s body, tumor cells can
be killed. (4) Cytokine-induced killer (CIK) cell
therapy is based on the following principles: CIK
cells are novel, highly proliferative immune cells
with cytotoxic properties and some immunological
characteristics. These cells express CD3 and CD56
membrane proteins, resembling NK cells with
powerful antitumor activity typical of
T lymphocytes.227
Tumor vaccines are a therapeutic strategy for
boosting the immune system’s capacity to combat
cancer. These vaccines may contain tumorassociated antigens to assist the immune system
in recognizing and targeting cancer cells.
Notably, Provenge (Sipuleucel-T) is currently
the world’s first and only tumor vaccine
approved by the U.S. Food and Drug
Administration (FDA).228 Dendritic cell (DC)
vaccines have also made significant break­
throughs in many clinical trials.229
Molecular targeted therapy focuses on reversing
malignant biological behaviors at the molecular
level, targeting processes that can lead to cellular
transformation, such as cell signaling pathways,
oncogenes, tumor suppressor genes, cytokine
receptors, antitumor angiogenesis, and suicide
genes.230 This approach aims to control tumor
cell growth and achieve complete tumor regression.
This approach offers high selectivity at the mole­
cular and cellular levels by efficiently and selec­
tively targeting tumor cells while minimizing
damage to normal tissues. Molecular targeted ther­
apy drugs can be broadly categorized into the fol­
lowing two types: monoclonal antibodies and small
molecules. Monoclonal antibodies are a key com­
ponent of biological targeted therapy.
Immunoadjuvants are adjunctive therapies that
enhance the activity of the immune system to com­
bat cancer better. These adjuvants can be used in
conjunction
with
other
immunotherapy
231
methods.
Cytokine therapy takes advantage of immune
modulators that can help strengthen the immune
system’s response against certain tumors.
Commonly used cytokines in antitumor immu­
notherapy include IL-2, IL-12, INF-γ, and TNF.232
4.2. The gut microbiome and tumor
immunotherapy
In recent years, tumor immunotherapy has devel­
oped rapidly and garnered attention due to its high
specificity and possible long-term effectiveness.4
The most extensively researched immunotherapy
strategies are PD-1/PD-L1 and CTLA-4 immune
checkpoint inhibitors. Immunotherapy can pre­
cisely identify and target tumor cells without caus­
ing significant harm to healthy cells. This treatment
has shown potential efficacy in various cancer
types, including melanoma,233,234 lung cancer,235
colorectal cancer,236 and lymphoma.237 Some
patients achieve long-term clinical responses after
immunotherapy and maintain resistance to tumors
even after the treatment process.238 However, the
major limitation of tumor immunotherapy is that it
does not work for all cancer patients. Some indivi­
duals may not exhibit a significant response to
GUT MICROBES
treatment. A study conducted in Israel involved 10
individuals with advanced-stage melanoma whose
cancer had continued to progress despite prior
treatment with a checkpoint inhibitor.239
Substantial evidence demonstrates that intestinal
microorganisms have the potential to impact clin­
ical responses to ICIs and their side effects in
a variety of cancer types.5
There is clear evidence indicating that the gut
microbiota plays a crucial role in shaping the
immune system, is closely related to innate and
adaptive immunity, and can impact the clinical
responses and adverse effects of immune check­
point inhibitors in various cancer types.240,241
Components within the gut microbiota can mod­
ulate the host’s antitumor immune response.184,242
Several studies have indicated the role of the gut
microbiota in regulating the effectiveness of
immune checkpoint blockade therapy.185 Recent
research by a Canadian team explored the potential
of FMT from cancer-free donors to prevent immu­
notherapy resistance in individuals who had not
previously received such treatment. Twenty
patients with advanced melanoma were employed.
Three individuals responded completely after FMT
and immunotherapy, 13 partially responded, and
three had persistent disease.243 Additionally, FMT
was utilized to evaluate the impact of gut micro­
biota by transferring fecal microbial communities
obtained from responders and nonresponders into
a germ-free melanoma model mouse. Intriguingly,
researchers found that even without using anti-PDL1 drugs, transplanting fecal microbiota from
responders could lead to tumor shrinkage.
A synergistic effect was observed when fecal micro­
biota transplantation was combined with anti-PDL1 treatment. However, the combination had no
antitumor response in nonresponders.243 In
another study, seven melanoma donors who had
achieved a durable response to immunotherapy
were employed. Another 16 patients with meta­
static melanoma, whose cancer had progressed fol­
lowing prior immunotherapy, were enrolled for
FMT with the donors’ feces. Among the 16 recipi­
ents, six exhibited a positive response, with three
achieving a complete response.200 In melanoma
patients who were resistant to anti-PD-1 therapy,
15
FMT from individuals who had responded effec­
tively managed to reinstate the tumor’s sensitivity
to PD-1 blockade. This led to beneficial alterations
in immune and microbial profiles within both the
gut and the tumor microenvironment.244,245
Distinct features were observed in the
responsive and nonresponsive melanoma
patients’ gut microbes. Patients who responded
to treatment exhibited elevated levels of uni­
dentified species from the Ruminococcaceae
and Faecalibacterium families, along with
Ruminococcus bicirculans and Barnesiella intes­
tinihominis. Conversely, nonresponders dis­
played
enrichment
in
Adlercreutzia
equolifaciens, Bacteroides thetaiotaomicron,
Bifidobacterium dentium, and unidentified spe­
cies from the Mogibacterium genus. 246
However, Matson et al. discovered a strong
connection between the clinical response and
commensal
microbial
composition.
Furthermore, they identified that E. faecium,
Collinsella aerofaciens, and Bifidobacterium
longum were common in fecal samples from
melanoma patients who positively responded
to immunotherapy therapy. Transplanting
fecal samples from responding patients into
germ-free mice enhanced T-cell responses and
increased the effectiveness of anti-PD-L1
therapy. 184 A parallel study delved into the
gut microbial populations of melanoma
patients and discovered that the abundance of
Ruminococcaceae species was linked to clinical
responses
to
checkpoint
inhibition. 183
McCulloch et al. proposed that an undesirable
gut microbiota promotes systemic inflamma­
tion and resistance factors that affect immunity
and the response to immunotherapy. They also
noted that the high abundance of Streptococcus
species was associated with treatment-related
adverse events and a shorter progression-free
survival.247 In other research studies, the anti­
tumor effects of CTLA-4 blockade depended on
specific
Bacteroides
species,
such
as
B. thetaiotaomicron and B. fragilis.242 In con­
trast, the presence of the Bifidobacterium genus
was positively linked to the effectiveness of PDL1 ligand PD-1 blockade.248 Additionally, the
16
S. JIANG ET AL.
Figure 4. The primary mechanism of probiotics enhances the effectiveness of tumor immunotherapy.
presence of A. muciniphila in stool samples
positively correlated with clinical responses to
ICIs in both patients and mouse models.185
5. Probiotics regulate the immune system by
mediating the gut microbiome
Probiotics are a category of beneficial, active
microorganisms that can regulate the gut micro­
biota and the immune system through multiple
mechanisms. (ⅰ) Probiotics can inhibit the coloni­
zation and proliferation of pathogenic bacteria in
the gut through competitive exclusion, the produc­
tion of antimicrobial substances, including pep­
tides, bacteriocins, and butyrate,249,250 and
modification of the gut environment. Probiotics
can increase the abundance of microorganisms in
the gut that produce short-chain fatty acids
(SCFAs).251 These SCFAs, essential metabolic
byproducts of gut microbes, influence immune
cells’ metabolism and signal transduction. (ⅱ)
Probiotics play a role in maintaining gut perme­
ability and enhancing intestinal barrier function.
They achieve this by promoting mucus secretion,
increasing tight junction proteins, or reducing
intestinal permeability. Research has demonstrated
that Lactobacillus rhamnosus GG (LGG) can
directly interact with intestinal epithelial cells
(IECs) and preserve the integrity of the epithelial
barrier.252 Studies have shown that probiotics
induce goblet cells to secrete mucins and inhibit
pathogen adhesion.253 Lactobacillus plantarum
BMCM12 can secrete extracellular proteins that
weaken pathogen adhesion, safeguarding the
intestinal barrier.254 (ⅲ) Probiotics also modulate
intestinal immune function by interacting with
various cell types, including IECs, DCs, T cells,
and B cells, by influencing their differentiation,
GUT MICROBES
activation, proliferation, and secretion. Probiotics
engage with IECs or immune cells associated with
the lamina propria through Toll-like receptors.
This interaction leads to the release of different
cytokines and chemokines, activating both innate
immune responses and cytokine release by T cells
and stimulating mucosal immune cells.255,256
Research has indicated that probiotics entering
the gut can stimulate the production of IgA
antibodies.257 Oral intake of probiotics effectively
increases the number of IgA+ cells in the intestinal
lamina propria, thereby reinforcing and sustaining
immune surveillance in mucosal areas distant from
the gut and promoting the maturation of humoral
immune mechanisms.255,258 Probiotics can also
augment the number of macrophages and DCs in
the lamina propria and enhance their functionality
over a specific timeframe. One study demonstrated
that specific Lactobacillus probiotic strains acti­
vated an in vitro inflammatory response in macro­
phages by synthesizing proinflammatory
mediators, including cytokines and reactive oxygen
species (ROS), and were involved in signaling path­
ways such as nuclear factor-kappa B (NF-kB) and
Toll-like receptor 2 (TLR2).257
Probiotics can also impact the host’s immune
response by altering the composition and diversity
of the gut microbiota. Probiotics can increase the
abundance of beneficial bacteria. Treatment with
a mixture of Bifidobacterium can modify the gut
microbial community, significantly increasing the
population of other probiotic species, such as
Lactobacillus, Kosakonia, and Cronobacter. These
beneficial bacteria can produce metabolites,
including SCFAs, which favor immune regulation.
Furthermore, the altered symbiotic community
enhances the adaptability of mitochondria and
intestinal Tregs’ metabolic and inhibitory functions
mediated by IL-10. This contributes to maintaining
regional immune homeostasis in patients under
conditions of CTLA-4 blockade.259 Treg cells are
a key mechanism through which probiotics exert
their beneficial effects. The mechanism by which
probiotics regulate and alleviate inflammatory dis­
eases and atopic dermatitis in neonates and infants
was associated with the induction or expansion of
Tregs and the manipulation of mucosal DCs to
promote regulatory function.260,261 Furthermore,
another study has indicated that bacterial strains
17
from Clostridia clusters IV, XIVa, and XVIII play
a pivotal role in Treg development in healthy mice,
protecting against pathogens. Additionally, species
within the Clostridia group, including
F. prausnitzii, may promote Treg differentiation
by producing SCFAs.
Beyond this, the next-generation probiotics
(NGPs), such as the human commensal bacteria
F. prausnitzii or A. muciniphila, have emerged as
promising candidates. These strains may offer bet­
ter adaptability to the gut, are being utilized to
alleviate obesity, inflammatory bowel disease
(IBD), and cancer, and investigate disease
mechanisms.262 Research has shown that the poly­
saccharide A (PSA) produced by F. prausnitzii can
modulate the host’s immune system in terms of
both health and disease. PSA also plays a critical
role in developing the mammalian immune system
and activating CD4+ T cells.263 F. prausnitzii can
enhance the effects of tumor immunotherapy and
reduce its side effects.242 Additionally, the presence
of A. muciniphila can improve the clinical efficacy
of PD-1 inhibitor treatment in patients with
NSCLC.264
6. Probiotics enhance tumor immunotherapy
via mediating the gut microbiome
The gut microbiota plays a pivotal role in develop­
ing and maturing the host’s innate and adaptive
immune systems.265 Given the adaptable character­
istics of the microbiome, adjusting the microbiota
has recently become an appealing approach with
the potential to address resistance to tumor immu­
notherapy in patients. On the one hand, the FMT
strategy can be used to transplant the fecal micro­
biota of responders. On the other hand, increasing
research focuses on the regulatory effects of pro­
biotics on the gut microbiota and their promoting
effect with tumor immunotherapy (Figure 4).
Routy et al. pinpointed that A. muciniphila could
mediate the connection between immunotherapy
and treatment response. They found that orally
administering A. muciniphila after fecal microbiota
transplantation with feces from nonresponders
reinstated the effectiveness of PD-1 blockade
through an interleukin-12-dependent mechanism.
This process facilitated the recruitment of CCR9
+CXCR3+CD4+ T lymphocytes into epithelial
18
S. JIANG ET AL.
tumors.185 Preclinical oral probiotics in mice
showed promising results in melanoma and blad­
der
cancer
studies.
Administration
of
Bifidobacterium enhanced tumor control signifi­
cantly. This approach nearly eradicated the tumors
when combined with CD274 (PD-L1) blockade.
The main contributing factors to success were the
improved function of DCs and the recruitment of
CD8+ T cells to the tumor microenvironment.248
Le Noci et al. demonstrated that Lactobacillus
rhamnosus could counteract immunosuppression
and hinder the implantation of lung tumors.
Moreover, tumor metastases were reduced when
both antibiotics and probiotics were employed.
These collective results suggest that the microbiota
in the local environment plays a crucial role in the
development of lung cancer by influencing the
local immune response.266 Supplementation with
Lactobacillus pentosus Probio-M9 probiotics pro­
moted the production of beneficial metabolites,
such as butyric acid, in the gut by increasing ben­
eficial microbes such as Lactobacillus and
Bifidobacterium. In particular, this bacterium accu­
mulated beneficial metabolites, including αketoglutarate, N-acetylglutamine, and pyridoxol
derived from blood sources, enhancing the antiPD-1 immune therapy response.14
In the context of colon cancer, a different study
examined the impact of intratumor microbiota on
CD47-based cancer immunotherapy. Shi et al.
orally administered Bifidobacterium and discov­
ered that Bifidobacterium from the colon accumu­
lates within tumor sites and enhances local antiCD47 treatment through the STING pathway.267
Additionally, Iida et al. demonstrated that admin­
istering Alistipes shahii through oral gavage
restored the immunotherapeutic response against
colon tumors in mice previously treated with
antibiotics.268
In melanoma, C57 mice were orally administered
a combination of commensal Bifidobacterium,
including B. breve and B. longum, through gavage.
This treatment promoted antitumor immunity and
enhanced the effectiveness of anti-PD-L1 therapy.248
A recent study published in Cell introduced the only
known probiotic capable of homing to tumors and
exerting synergistic effects with immunotherapy.
Lactobacillus reuteri (Lr) was found to migrate to
and colonize melanoma tumors readily and released
the dietary tryptophan-derived metabolite indole3-carbaldehyde (I3A), which stimulated the produc­
tion of interferon-gamma by CD8+ T cells, leading to
the killing of cancer cells and thereby enhanced the
efficacy of ICIs. The antitumor immune response
induced by I3A secreted by Lr relies on the AhR
receptor found on CD8+ T cells.15
7. Conclusion and outlook
This article explores the relationship between gut
microbiota and cancer from the perspectives of gut
microbial communities and tumors. We summarized
the disruption of gut microbiota, particularly in can­
cer patients, delving into the underlying mechanisms
behind this imbalance. Additionally, the microbial
biomarkers that appear in cancer diagnosis and prog­
nosis were addressed. Furthermore, we delved into
how the gut microbiota affected the tumor microen­
vironment, including the composition of tumor-asso­
ciated microbial communities and their influence on
cancer development. By untangling the intricate rela­
tionships among microbes, the tumor microenviron­
ment, and cancer cells, valuable insights can be gained
for potential cancer treatments, including targeted
and personalized therapies, to maximize the efficacy
of anticancer treatments. In addition, we highlighted
recent advancements in using probiotics to enhance
the effectiveness of cancer immunotherapy.
Probiotics are a type of beneficial live microor­
ganism that benefits human health. They can regu­
late intestinal function, enhance immune system
function, and inhibit the growth and spread of
tumor cells. In recent years, numerous studies have
shown that probiotics can synergize with immune
checkpoint inhibitors (such as PD-1, PD-L1, or
CTLA-4 antibodies) in various ways to modulate
the immune responses of cancer patients, enhancing
the effectiveness and tolerance of immunotherapy.
On the one hand, probiotics can regulate cancer
patients’ gut microbiota and immune microenviron­
ment by promoting the secretion of immune factors
at the tumor site, thus influencing the body’s
response to immune inhibitors and alleviating the
treatment side effects caused by chemotherapy. On
the other hand, probiotics can also migrate to tumor
sites and exert their inhibitory effects, including
stimulating the secretion of immune cell factors
and producing antitumor substances such as I3A.
GUT MICROBES
This comprehensive review offers valuable insights
into the dynamic interactions between gut microbial
communities, probiotics, and tumors.
Despite promising research results, the relation­
ship between cancer immunotherapy and probiotics
still requires further investigation to clarify their effi­
cacy and safety. Research on the promoting effects of
probiotics on cancer immunotherapy continued to be
a hot topic in human health. Probiotics could emerge
as a novel adjuvant for cancer treatment and be
combined with other drugs or therapeutic approaches
to improve cancer patient’s prognosis and quality of
life. Furthermore, by maintaining a healthy gut
microbiome, probiotics might have contributed to
the prevention of tumor development or the slowing
of tumor progression, providing new avenues for
early tumor intervention. Additionally, different
types of tumors and patients may respond differently
to probiotics, emphasizing the importance of perso­
nalized treatment and optimizing the potential of
immunotherapy strategies in the future.
FADA
ACI
CAR-T
TIL
NK
CIK
DC
FDA
SCFAS
LGG
IECS
ROS
NF-kb
TLR2
Lr
19
Antigen adhesin A
Adoptive cellular immunotherapy
Chimeric antigen receptor T-cell
Tumor-infiltrating lymphocyte
Natural killer
Cytokine-induced killer
Dendritic cell
U.S. Food and Drug Administration
Short-chain fatty acids
Lactobacillus rhamnosus GG
Intestinal epithelial cells
Reactive oxygen species
Nuclear factor-kappa B
Toll-like receptor 2
Lactobacillus reuteri
Acknowledgments
This research was supported by the National Natural Science
Foundation of China [32222066] and the Hainan Province
Science and Technology Special Fund under Grant
[GHYF2023001].
Abberivation
TME
ICIS
I3A
CRC
BFT
CNF1
pks+
DSBS
AUC
SNV
INOS
GERD
HCC
LPS
ICC
CCA
PDA
PDAC
ICC
BC
EOC
FMT
SCC
OSCC
Tumor microenvironment
Immune checkpoint inhibitors
Indole-3-carbaldehyde
Colorectal cancer
B. Fragilis toxin
Cytotoxic necrotizing factor 1
Polyketide synthase-positive
Double-strand DNA breaks
Receiver-operating characteristics curve
Single nucleotide variant
Inducible nitric oxide synthase
expression
Gastroesophageal reflux disease
Hepatocellular carcinoma
Lipopolysaccharide
Intrahepatic cholangiocarcinoma
Cholangiocarcinoma
Pancreatic ductal adenocarcinoma
Pancreatic adenocarcinoma
Intrahepatic cholangiocarcinoma
Breast Cancer
Epithelial ovarian cancer
Fecal microbiota transplantation
Small-cell carcinoma
Oral squamous cell carcinoma
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
The work was supported by the National Natural Science
Foundation of China [32222066] and the Hainan Province
Science and Technology Special Fund under Grant
[GHYF2023001].
ORCID
Shuaiming Jiang
http://orcid.org/0000-0002-9384-9200
Jiachao Zhang
http://orcid.org/0000-0001-8099-6749
Credit authorship contribution statement
Shuaiming Jiang: Conceptualization, Writing – original & edit­
ing, Visualization. Wenyao Ma: Writing – original & editing,
Visualization. Chenchen Ma: Data curation, Investigation,
Visualization. Zeng Zhang: Investigation, Visualization. Wanli
Zhang: Conceptualization, Writing – review & editing. Jiachao
Zhang: Conceptualization, Writing – review & editing, Funding
acquisition.
20
S. JIANG ET AL.
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