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TYPE Review
PUBLISHED 16 February 2023
DOI 10.3389/fnut.2023.1113739
OPEN ACCESS
EDITED BY
Peng Liu,
Sun Yat-sen University, China
REVIEWED BY
Paolo Paoli,
University of Florence, Italy
María A. García,
University of Concepcion, Chile
*CORRESPONDENCE
Aihua Gong
ahg5@mail.ujs.edu.cn
†These authors have contributed equally to this
work and share first authorship
SPECIALTY SECTION
This article was submitted to
Nutritional Immunology,
a section of the journal
Frontiers in Nutrition
RECEIVED 01 December 2022
ACCEPTED 30 January 2023
PUBLISHED 16 February 2023
CITATION
Li Z, Wang Q, Huang X, Yang M, Zhou S, Li Z,
Fang Z, Tang Y, Chen Q, Hou H, Li L, Fei F,
Wang Q, Wu Y and Gong A (2023) Lactate in the
tumor microenvironment: A rising star for
targeted tumor therapy.
Front. Nutr. 10:1113739.
doi: 10.3389/fnut.2023.1113739
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©2023 Li, Wang, Huang, Yang, Zhou, Li, Fang,
Tang, Chen, Hou, Li, Fei, Wang, Wu and Gong.
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terms.
Lactate in the tumor
microenvironment: A rising star for
targeted tumor therapy
Zhangzuo Li1,2†, Qi Wang3† , Xufeng Huang4†, Mengting Yang2†,
Shujing Zhou5, Zhengrui Li6,7,8, Zhengzou Fang2, Yidan Tang5,
Qian Chen2, Hanjin Hou2, Li Li2, Fei Fei2, Qiaowei Wang2, Yuqing Wu2
and Aihua Gong1,2*
1Hematological Disease Institute of Jiangsu University, Aliated Hospital of Jiangsu University, Jiangsu
University, Zhenjiang, China, 2Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang,
China, 3Department of Gastroenterology, Aliated Hospital of Jiangsu University, Jiangsu University,
Zhenjiang, China, 4Faculty of Dentistry, University of Debrecen, Debrecen, Hungary, 5Faculty of Medicine,
University of Debrecen, Debrecen, Hungary, 6School of Medicine, College of Stomatology, Shanghai Jiao
Tong University, Shanghai, China, 7National Center for Stomatology and National Clinical Research Center
for Oral Diseases, Shanghai, China, 8Shanghai Key Laboratory of Stomatology, Shanghai, China
Metabolic reprogramming is one of fourteen hallmarks of tumor cells, among which
aerobic glycolysis, often known as the “Warburg eect,” is essential to the fast
proliferation and aggressive metastasis of tumor cells. Lactate, on the other hand, as
a ubiquitous molecule in the tumor microenvironment (TME), is generated primarily
by tumor cells undergoing glycolysis. To prevent intracellular acidification, malignant
cells often remove lactate along with H+, yet the acidification of TME is inevitable.
Not only does the highly concentrated lactate within the TME serve as a substrate to
supply energy to the malignant cells, but it also works as a signal to activate multiple
pathways that enhance tumor metastasis and invasion, intratumoral angiogenesis,
as well as immune escape. In this review, we aim to discuss the latest findings on
lactate metabolism in tumor cells, particularly the capacity of extracellular lactate
to influence cells in the tumor microenvironment. In addition, we examine current
treatment techniques employing existing medications that target and interfere with
lactate generation and transport in cancer therapy. New research shows that targeting
lactate metabolism, lactate-regulated cells, and lactate action pathways are viable
cancer therapy strategies.
KEYWORDS
lactate, tumor microenvironment, metabolic, immunity, immune cells
1. Introduction
The cellular transformation includes uncontrolled cell proliferation, resistance to cell death,
immune evasion, and evasion of growth inhibitory activity, ultimately leading to cancer
formation (1,2). Furthermore, it has been observed that, as part of the tumor survival machinery,
tumor cells adapt to different survival challenges by altering their metabolism, a feature now
considered a hallmark of cancer (1–3). Most normal tissues obtain energy through aerobic
respiration in the presence of oxygen, while energy is provided only in the absence of oxygen
through glycolysis. However, in tumor tissues, tumor cells select a low adenosine triphosphate
(ATP)-generating mode of glycolysis to provide energy for their rapid growth and proliferation,
even under adequate oxygen conditions, a specific phenomenon now known as the Warburg
effect (4,5), also known as glycolysis. The reasons why tumor cells choose this seemingly
uneconomical method of metabolism include the fact that glycolysis allows tumor cells to better
adapt to fluctuations in oxygen partial pressure. The intermediates of glycolysis can be used by
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Li et al. 10.3389/fnut.2023.1113739
tumor cells to synthesize macromolecules such as proteins, nucleic
acids, and lipids needed for cell construction, thus maintaining the
growth and proliferation of the tumor cells themselves, although
glycolysis produces less ATP than aerobic respiration, it produces
ATP at a higher rate to meet the energy demands of rapid tumor
growth, and using glycolysis as the primary mode of energy supply
reduces the mitochondrial of the electron transport chain (6), the
production of anaerobic glucose glycolysis reduces the production
of free radicals (ROS) and thus reduces the toxicity to tumor cells
(6). Cancer cells use large amounts of glucose as their energy source,
leading to the accumulation of extracellular lactate, which can alter
the metabolic patterns of multiple cells, including immune cells,
within the tumor microenvironment (TME) (7). In the early stages
of tumor growth, immune cells recruited and activated by tumor
cells can form a tumor-suppressive inflammatory microenvironment
that hinders tumor progression. However, as tumor cells continue to
proliferate and continue the immune activation response, the TME
undergoes dynamic changes: immune effector cells become depleted
or remodeled thus failing to function properly. An important cause
of these changes is the high concentration of lactate produced by
the Warburg effect, which affects the differentiation, metabolism, and
function of tumor-infiltrating immune cells through several pathways
(8). For many years lactate has been considered a waste metabolite,
but it is now clear that lactate plays an irreplaceable role in promoting
tumor cell survival, oncogene signaling (9), inflammation, metastasis
(10), tumor resistance (11), immunosuppression (12,13), and many
other oncogenic processes. In this review, we briefly discuss the role
of lactate in tumor progression, particularly its role in the metabolic
microenvironment, immune microenvironment, and metastasis. We
conclude that studies of targeted lactate therapeutic strategies and
transport and combination therapy with other agents offer a new
way of thinking to attack cancer and discuss the potential for clinical
translation of lactate therapy.
2. The role of lactate in promoting
tumor progression
2.1. The role of lactate in tumor cell
metabolism
It has been found that lactate can stabilize HIF-2αand activate c-
Myc, which results in an up-regulation in the expression of glutamine
transporter (ASCT2) and GLS1, and an enhancement in glutamine
uptake as well as catabolism (14). Damiani et al. found that tumor
cells can maximize the use of α-ketoglutaric acid (α-KG), a catabolite
of glutamine, into the TCA cycle, which is converted to pyruvate by
malase and finally to lactate by LDHA (15) (Figure 1). The above
preliminary clues suggest that glycolysis and glutamine catabolism
pathways may be interdependent and jointly maintain the interstitial
phenotype of tumor cells, but it is not clear whether there is a
regulatory relationship between key enzymes LDHA and GLS1.
As a “mitochondrial vent”, PYCR dissipates electron aggregation
by oxidizing NADH to NAD+, allowing the TCA cycle to proceed
independently of oxygen consumption (16). This is also necessary
for the oxidation of NADH produced by the glycolysis pathway (17).
In addition, early reports found that lactate could directly inhibit
the activity of proline oxidase (PRODH/POX) (18), and indirectly
negatively regulates the expression of PRODH/POX, while reducing
the degradation of Pro (19–21). Lactate can activate c-Myc to up-
regulate the expression of PYCR, thus up-regulating the expression
of proline. The above results suggest that lactate plays a positive
regulatory role in the process of the Pro synthesis pathway.
2.2. Eect of lactate on tumor immunity
2.2.1. Lactate and innate immune cells in the TME
Through the activity of its stromal cells, TME is in a state
of continuous modification with the progress of the tumor. As
an important site for tumor cells to survive, TME has a complex
composition, including immune cells, cancer associated fibroblasts
(CAFs), vascular endothelial cells, and other types of cells, an
extracellular matrix, and a large number of active molecules.
On the one hand, innate immune cells present in TME, including
macrophages, neutrophils, dendritic cells, natural lymphoid cells,
invariant natural killer cells, and myeloid-derived suppressor cells, as
well as adaptive immune cells including T and B cells, are responsible
for detecting and eliminating cancer cells (22,23). On the other hand,
tumor cells can recruit immunosuppressive cell populations into
TME by secreting anti-inflammatory cytokines, where they directly
suppress immune responses (24) (Figure 2).
Invariant natural killer T (iNKT) cells are at the forefront
of the anti-tumor immune response. They can not only kill
target cells directly through antigen recognition but also enhance
anti-tumor immune responses by inhibiting tumor-associated
macrophages (TAMs) and promoting the activation of NK and
Cytotoxic T lymphocytes (CTLs) (25–28). PPARγand BTB–zinc
finger transcriptional regulator PLZF synergically promote lipid
biosynthesis of iNKT cells after activation through enhancing
transcription of SERBP1. In the tumor microenvironment with high
concentrations of lactate, the expression of PPARγin intratumoral
iNKT cells will be inhibited, thus consequently reducing their
cholesterol synthesis. And cholesterol is necessary for iNKT cells to
produce the optimal IFN- γ(29).
Tumor-associated macrophages are the most numerous subsets
in the immune microenvironment, accounting for more than 50%
of the immune cells in the tumor microenvironment (30). There
are two main phenotypes of TAM: M1-TAM (tumor suppressor)
has the function of antigen presentation and can activate immune
factors, which is beneficial to anti-tumor immune response. M2-
TAM (tumor-promoting type) can inhibit the inflammatory reaction,
shield tumor immune surveillance, and promote tumor growth
and metastasis (31). Lactate can activate the MCT-HIF1αpathway
and promote macrophages to M2 polarization, which further
complements the regulatory mechanism of macrophage polarization
(32). The expression of IL-12 in M2-TAM decreased and the
expression of IL-10 increased, which could promote the occurrence
and growth of tumors. Experiments have shown that TAMs can
regulate cancer progression through a variety of mechanisms (33).
Lactate can also inhibit the degradation of HIF2αby activating
mTORC1 in macrophages, thus promoting tumor development
(34). Lactate inhibits the activation of YAP and nuclear factor-
kB through a GPR81-mediated signal and reduces the production
of pro-inflammatory cytokines in macrophages, thus inhibiting
the pro-inflammatory response of macrophages to LPS stimulation
(35). Regulation of lactate levels can promote the transformation
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FIGURE 1
Glycolysis and glutamine metabolism. Glucose is catabolized to pyruvate in the cytoplasm. Conversion of lactate from pyruvate stabilizes HIF-2a, which
then stabilizes c-Myc protein expression in the nucleus. c-Myc promotes glutamine transporter protein 2 (ASCT2) expression. Glutaminase 1 (GLS1)
catalyzes the breakdown of glutamine to glutamate in the mitochondria. In the mitochondrial matrix, glutamate is converted to a-KG and enters the
tricarboxylic acid cycle.
of macrophages from M1 to M2 and upregulate PD-L1 to help
tumor immune escape (36). In addition, studies have shown that
reducing the level of lactate in tumors can inhibit the polarization
of macrophages to M2, thus inhibiting the secretion of CCL17 and
finally inhibiting the invasion of pituitary adenomas (37).
Myeloid-derived suppressor cells (MDSCs) represent a group
of expanded, heterogeneous immature myeloid cells that can be
subdivided into monocytic MDSCs (M-MDSCs) and granulocyte
MDSCs (G-MDSCs). These two MDSC subsets are thought to
have a significant ability to block innate and adaptive immunity
(38). Several studies have shown that lactate in the acidic tumor
metabolic microenvironment induces increased HIFαin MDSCs,
leading to increased expression of programmed death ligand 1 (PD-
L1), which regulates the development of myeloid cells (39,40).
Notch-RBP-J signaling plays a key role in determining cell fate
and plasticity, and it is highly conserved (41). Recent studies have
shown that myeloid-specific activation of Notch/RBP-J signaling
could inhibit the transcription of the lactate transporter MCT2
through its downstream molecule Hes1, leading to a decrease in
intracellular lactate levels and inhibition of granulocyte MDSC (G-
MDSC) differentiation. Combining Notch activation and MCT2
inhibition in myeloid cells represses tumor growth (37).
DCs are the most functional specialized antigen-presenting cells
found in vivo and they play a crucial role in initiating specific
antitumor T-cell responses (42). One of the main functions of DCs
is to activate the immune response by processing and presenting
antigens through the MHC-II and MHC-I (43). The accumulation of
lactate in tumors prevents the differentiation of DCs and makes the
cells tolerant (44), limits the ability of DCs to recognize and present
antigens (45), inactivates cytokines released by DCs, and promotes
the production of an important immunosuppressive cytokine, IL-10,
by DCs and inhibits the secretion of the pro-inflammatory factor
IL-12 (46,47). The effect of lactate on DC cells was also reversible
when lactate was neutralized with NaOH to pH 7.4, showing that the
inhibitory effect of lactate on DC activation disappeared (48).
Neutrophils are derived from bone marrow hematopoietic stem
cells and have unique morphology because of their lobular nuclei, and
can be determined by the phenotypes expressed on the cell surface.
Neutrophils account for a significant proportion of the primary
tumor immune cell infiltration (49). Recent studies have shown that
neutrophils have both anti-tumor and tumor-promoting effects in
cancers (50). N1 neutrophils are thought to have the potential to kill
tumor cells due to the activation of immune factors such as TNF-α,
ICAM-1, and FAS, resulting in elevated levels of immune factors and
direct antibody-dependent cytotoxicity (51). N1 neutrophils can also
exert anti-tumor effects indirectly through the regulation of T-cell
function (52). It has been shown that N1 neutrophils exert antitumor
effects through the release of neutrophil elastase (53). Neutrophils
can undergo phenotypic and functional remodeling in response to
lactic acid, which is the effect of N2. N2 neutrophils release a variety
of pro-tumor factors and participate in promoting tumorigenesis
and progression through multiple mechanisms. N2 neutrophils can
release a variety of proteases that promote malignant proliferation
and metastasis of tumor cells. matrix metalloproteinases (MMPs)
mainly regulate tumor angiogenesis and metastasis. Blocking or
reducing the production of these proteases is expected to achieve the
purpose of inhibiting tumor progression (54).
2.2.2. Lactate and T cells in the TME
T cells have long been thought to be effective against tumor
cells and form lasting immunity, and their specificity to antigens
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FIGURE 2
Eect of lactate in the regulation of the immune response. The lactate in the TME aects the dierentiation, metabolism, and function of innate and
adaptive tumor-infiltrating immune cells through multiple pathways and inhibits anti-tumor immune responses. The lactate secreted by tumor and
stromal cells acidifies the TME and promotes tumor cell proliferation and metastasis.
expressed by tumors is crucial (55), but other inherent characteristics
of T cells, such as persistence, longevity, and function, also play an
important role in determining the effectiveness of immunotherapy
(56). Tumor-derived lactate reduces CTL recruitment in TME and
further inhibits the function of infiltrating CTL in TME by impairing
its chemotactic and respiratory activities (57). Quinn et al. have
reported that the inhibitory effect of lactate on the proliferation of
effector T cells does not depend on acidity, which is achieved by the
transition from NAD+to NADH (lactate-induced reductive stress).
This impairs glycolysis and the production of glucose-derived serine,
which is necessary for effector T-cell proliferation (58). Tumor cells
often exhibit uncontrolled metabolic processes, leading to a tumor
microenvironment of metabolite depletion, hypoxia, and acidity,
which makes it difficult for effector T cells to exert their lethal
function. Recent studies have also found that lactate can promote
the stem cell-like characteristics of CD8+T cells, thus playing an
anti-tumor immune role in cancer treatment. This shows that lactate
has two sides in T cell anti-tumor immunity (59). Regulatory T
Cells (Tregs) also play an important role in immune homeostasis,
and unlike other immune cells, Tregs have increased activity and
recruitment in acidic TME, becoming a major barrier to anticancer
immunity (60). Lactate can be used as a carbon fuel source for Treg
to maintain its high inhibition ability. Inhibition of Monocarboxylate
transporter 1 (MCT1), direct targeting of lactate metabolism, or
inhibition of tumor acidity may break the metabolic symbiosis
between tumor cells and Treg cells, thus reducing the Treg barrier
of tumor immunity and enhancing the killing function of effector T
cells (61).
2.2.3. Lactate and CAFs in the TME
Cancer-associated fibroblasts (CAFs) are the predominant
stromal cells in TME (62,63). A vast number of studies have found
that CAFs play a multifaceted function in tumor growth (63–66).
They could not only provide ATP to adjacent cancer cells, but also
regulate the tumor cells and tumor microenvironment by secreting
various growth factors, cytokines, and chemokines [48], and prevent
the deep infiltration of drugs and immune cells into tumor tissue
by shaping the tumor extracellular matrix and forming a drug or
therapeutic immune cell permeation barrier, thereby diminishing
the therapeutic effects of the anticancer drugs (67,68). In terms of
offering energetic sources for tumor cells, CAFs emit a substantial
quantity of lactate through glycolysis to the tumor cells which in turn
use it as a fuel to support their physiological activities (69). A recent
study demonstrated evidence in which the tumor-secreted lactate
downregulates p62 in stromal fibroblasts, which essentially induces
the CAF phenotype (70,71).
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3. Mechanism of lactate inhibition of
antitumor response
3.1. Gene regulation by histone lactylation in
tumor cells
Lactate modification (lactylation) is a histone post-translational
modification reported by Zhang et al. for the first time, which plays
a role in gene transcriptional regulation (72). Follow-up studies
have further confirmed that protein lactylation is an important
way for lactate to exert its function and participate in cellular
life activities such as glycolysis-related cell function, macrophage
polarization, nervous system regulation, and so on (73–75). The
discovery of histone lactylation has pointed out a new direction
for the research on the participation of tumor cell metabolites in
the tumor, immunity, and other fields. The researchers found that
lactylation of histone lysine residue, as an epigenetic modification,
directly promoted chromatin gene transcription. The researchers
identified 28 lactate sites on the core histones of human and mouse
cells. Hypoxia and bacterial stimulation induce the production of
lactate through glycolysis, and it acts as a precursor to promote
histone lactylation. Using M1 macrophages exposed to bacteria
as a model system, the researchers found that histone lactylation
and acetylation had different time dynamics. Stimulation of mouse
bone marrow-derived macrophages with lipopolysaccharide and
interferon γ(LPS+IFNγ) to simulate infection with Gram-negative
bacteria revealed that macrophages produced large amounts of
lactate and induced histone lactylation modifications at 16–24 h
of stimulation; while histone acetylation levels decreased at the
same time. In the late stage of M1 macrophage polarization, the
lactate modification of histones is enhanced, which induces steady-
state genes involved in wound healing, including Arg1. Overall,
these results suggest that the endogenous “Lactate clock” in M1
macrophages attacked by bacteria turns on gene expression to
promote balance in the body (67). Histone lactylation, therefore,
provides an opportunity to improve understanding of the function
of lactate and its role in various pathophysiological conditions,
including infection and cancer. A recent study has shown that histone
lactylation accelerates tumorigenesis by activating M6A interpreter
protein YTHDF2, which provides a new histone lactylation target for
the treatment of ocular melanoma (73). At the same time, it also links
histone modification with RNA modification, which provides a new
understanding of epigenetic regulation.
3.2. Lactate/GPR81 signaling in cancer cells
In recent years, the importance of lactate to the survival and
growth of cancer cells has been proven to be achieved in part by its
ability to activate the lactate receptor (HCAR1), which is also called
GPR81. GPR81 is widely distributed in human tissues. GPR81 has
been identified as a lactate receptor (75). It is expressed in a variety
of cell types, including adipocytes, brain cells, skeletal muscle cells,
and various cancer cells (76). Xie et al. clarified the transcriptional
mechanism of GPR81 expression regulation in cancer cells. Lactate
induces the transcription factor Snail/STAT3 pathway and up-
regulates GPR81 expression through autocrine regulation (77). A
study has emphasized the importance of GPR81 in tumor growth
and migration. GPR81 promotes cell proliferation and angiogenesis
in a PI3K/Akt/cAMP-dependent manner in breast cancer cells.
Silencing GPR81 and treating cells with PI3K inhibitors can reduce
angiogenesis in vitro, thus inhibiting tumor growth (78). Recent work
elucidates the up-regulation of PD-L1 in glucose-stimulated lung
cancer cells mediated by GPR81 through lactate dehydrogenase A
(LDHA). It is also proved that the activation of GPR81 reduces the
level of intracellular cAMP and inhibits the activity of protein kinase
A (PKA), resulting in the activation of transcriptional coactivator
TAZ. The interaction between TAZ and transcription factor TEAD
is the key to activating PD-L1 and inducing its expression (79).
Lactate helps to protect tumor cells from being attacked by T cells,
establishing the relationship between metabolic reprogramming of
tumor cells and tumor evasion of the immune response. Another
paper proved that immune cells are involved in the growth of GPR81-
dependent tumors. The antigen is GPR81 on the surface of DC
cells, and the activation of this receptor is related to the decrease
of cAMP, IL-6, and IL-12, and can down-regulate the expression
of MHCII on the cell surface (76). These findings suggest that
lactate from tumor cells activates GPR81 in dendritic cells and blocks
the expression of tumor-specific antigens to other immune cells.
This paracrine mechanism complements the autocrine mechanism
of PD-L1 induced by activating GPR81 in tumor cells in recent
years and provides an effective means for tumor cells to evade the
immune system. Therefore, blocking the GPR81 signal can promote
cancer immunotherapy. GPR81 is expressed in both tumor and the
surrounding immune cells at the same time, and the end result of
GPR81 activation is the promotion of angiogenesis, immune evasion,
and chemoresistance.
4. Anti-tumor metabolic therapeutic
strategies targeting lactate metabolism
4.1. Therapeutic strategies targeting lactate
metabolism
Tumor, composed of tumor cells and the TME, is currently a
major scientific challenge in the field of medicine. Traditional tumor
treatment methods include surgery, radiotherapy, chemotherapy,
and so on, but these methods may cause serious damage to the
surrounding normal tissue while killing tumor cells (80–84).
The Warburg effect is prevalent in various tumors and is
characterized by a predominantly glycolytic energy metabolism
in cancer cells under adequate oxygen conditions. The glycolytic
product lactate can activate many essential signaling pathways
in cancer cells, promoting survival, invasion, immune escape,
metastasis, and angiogenesis. Combining aerobic glycolytic targeted
therapy with other therapeutic approaches, such as immunotherapy
and chemotherapy, is promising for cancer treatment.
Lactate oxidase (LOD) can catalyze the oxidation of lactate
to pyruvate and hydrogen peroxide. The use of lactate oxidase
can catalyze the change of lactate present in large amounts in
tumors to H2O2, which not only dismantles the tumor immune
microenvironment but H2O2can be converted to highly toxic
hydroxyl radicals (•OH) bar catalyzed by other compounds, thus
killing tumor cells (85–87). The depletion of lactic acid in the
tumor microenvironment by lactate oxidase can improve the
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tumor immunosuppressive microenvironment and effectively inhibit
tumor growth.
LDH is mainly composed of different proportions of LDHA
and LDHB subunits, forming five different LDH tetramer isozymes
(LDH1−5). The main function of lactate dehydrogenase is to
convert pyruvate to lactate and NADH to NAD+. The up-regulated
expression of LDH can be detected in some tumor clinical samples
(88–91), while the downregulation of LDH can inhibit the growth
and migration of cells in vitro and affect the occurrence of tumors
in vivo (92). Recently, lactate dehydrogenase-A (LDH-A) has been
found to protect the dryness of cancer and recruit tumor-related
macrophages to promote breast cancer progression (93). The method
targeting lactate dehydrogenase is used to inhibit the production of
lactate in TME.
In mouse cancer models, knockout of LDHA, LDHB, or knockout
alone can inhibit tumor growth, highlighting their key role in tumor
metabolism (94–96). The R- (-) enantiomeric AT-101 of gossypol
acetate and its derivatives FX-11, Galloflavin, and N-hydroxyindolyl
compounds have been shown to give priority to the inhibition of
LDHA subtypes (21). In lymphoma and pancreatic cancer xenografts,
FX-11 can reduce cellular lactate production, induce oxidative stress,
and eventually lead to tumor cell apoptosis and inhibit tumor
progression (97). In prostate cancer, FX-11 as a single drug can also
effectively inhibit the glycolysis of tumor cells, and then inhibit the
growth of tumor cells (97). It is reported that Galloflavin can bind to
free LDHA and inhibit glycolysis in breast cancer cells, thus acting as
an anti-tumor agent (98).
The authors identified a new LDH inhibitor, NCI-006,
which overcomes many of the drawbacks of other inhibitors,
is highly targeted and is expected to have an effect in vivo
(92). N-hydroxyindole drugs have been shown to reduce
the growth of pancreatic and cervical cancer cells in vitro
(99). And when used in combination with gemcitabine, it
can increase the apoptosis rate of pancreatic cancer cell
lines (100).
MCTs is a proton-linked transporter responsible for transporting
several monocarboxylic acid metabolites, such as pyruvate, L-lactate,
and ketone bodies, across the plasma membrane with protons.
MCT1/4 subtypes are dominant in tumor metabolism (101). MCTs
are promising anticancer targets. The use of MCT1 inhibitors
or gene knockout can interfere with lactate-fueled respiration in
mitochondria (102). MCTs play an important role in the metabolic
homeostasis of the tumor microenvironment. MCT1 and MCT4 are
the most widely expressed MCT isoforms in cancer cells. MCT1
has a high affinity for lactate and is preferentially expressed in
respiratory cancer cells that take up lactate (101). In contrast,
MCT4 has a low affinity for lactate and is suitable for promoting
lactate export from glycolytic cancer cells, and its expression is
upregulated by hypoxia (103). The use of MCT1 inhibitors to
disrupt the communication between oxidative and glycolytic cancer
cells can inhibit the growth of breast cancer and promote the
death of myeloma cell lines (104–106). MCTs inhibitors have been
shown to reduce the invasive and migratory capacity of glioma
cells (107), cervical squamous carcinoma cells (108), melanoma cells
(109), triple-negative breast cancer cells (110) and pancreatic ductal
adenocarcinoma cells (109). MCTs inhibitors could reduce glycolysis,
lactic acid and tumor growth and allow the immune response to
remain strong with increased tumor infiltration with CD8+T and
NK cells (53,111).
As the research on TME has intensified, many kinds of synergistic
therapies based on TME modulation have proliferated and achieved
better therapeutic effects in mice. Recently, Zhou et al. simultaneously
utilized lactate oxidase (LOD) and Fe3O4nanoparticles (NPs) to
treat tumors (86). the synergism between LOD and Fe3O4can
increase the consumption of lactate and produce more H2O2, and
concurrently hydrogen peroxide (H2O2) is subsequently converted
to highly toxic hydroxyl radicals (•OH) catalyzed by Fe3O4NPs via
Fenton-like reactions to kill tumor cells. This ingenious strategy
showed an obvious inhibitory effect on tumor growth and resistance
to metastasis. Chen et al. effectively inhibited tumor growth and
resisted tumor metastasis by using metformin (Me) and fluvastatin
sodium (Flu) to interfere with lactate metabolism in tumor cells (112).
On the one hand, Me alters the gluconeogenesis pathway and inhibits
the tricarboxylic acid (TCA) cycle by inhibiting mitochondrial
respiration (113), leading to an increase in the conversion of
pyruvate to lactate. On the other hand, Flu inhibits lactate efflux,
leading to intracellular acidosis, which kills tumor cells (114).
Considering integrating cascaded enzymes and gene therapy, Tang
et al. creatively proposed a method that can effectively inhibit tumor
proliferation and angiogenesis even with the combined strategy
of lactate oxidase/catalase (LOD/CAT) and vascular endothelial
growth factor (VEGF) siRNA (SiVEGF) (115). The combination
of lactate depletion and VEGF silencing effectively inhibited the
migration of 4T1 cells in vitro and showed good anti-tumor and anti-
metastasis properties in vivo (116). A recent study has shown that
lactate degradation can be promoted with the assistance of lactate
oxidase (LOD) cationic polyethyleneimine (PEI) and nano-coated
with a certain amount of copper ion (PLNPCu). More importantly,
hydrogen peroxide (H2O2), a by-product of lactate degradation, can
be converted into anti-tumor ROS under the catalysis of copper
ions, which mediates immunogenic cell death (ICD) (117). With the
decrease of lactate in TME, the ICD process effectively promoted the
anti-tumor immune response of the 4T1 tumor model (the tumor
inhibition rate was 88%) (116). These strategies show a good anti-
tumor effect and verify the feasibility of endogenous lactate as one of
the key targets for tumor therapy. Although preclinical studies have
proved that glycolysis is effective in the targeted treatment of tumors,
their clinical transformation is still limited so far. The main reasons
that restrict the development of glycolysis targeting therapy include
metabolic heterogeneity and the damage of glycolysis targeting the
immune system.
4.2. Therapeutic strategies targeting immune
cells
Treatment of immune cells in the tumor microenvironment is
also a strategy. Although there are few reports of specific treatment
of immune cells, these reports have shown encouraging results in
different studies. Several methods have provided promising prospects
focused on targeting immune cells. INKT cells play an important
role in the clearance of tumor cells (26–28). However, the tumor
microenvironment affects the metabolism of INKT cells and hinders
their anti-tumor functions. Fu et al. demonstrate that restoring lipid
synthesis via activating PPARγby using pioglitazone recovers αGC-
induced IFN-γproduction and significantly improves the efficacy
of iNKT cell-based immunotherapy against tumors. Importantly,
Frontiers in Nutrition 06 frontiersin.org
Li et al. 10.3389/fnut.2023.1113739
Pioglitazone has been already used in the treatment of type 2 diabetes,
which proves its potential application in clinical antineoplastic
therapy (29). This strategy of enhancing the antitumor efficacy of
iNKT cell-based immunotherapy by promoting lipid biosynthesis is
highly promising for clinical translation.
HIF1αcan directly regulate many M2-related genes, including
CD163 and ARG1 (118). Knockdown of HIF1αcan greatly impair
lactate-induced M2 polarization. By inhibiting the CCL17 released
by TAM, they can reduce the volume of prostate cancer, reduce the
invasiveness of the tumor, and the susceptibility to postoperative
recurrence (37). Tumor-derived lactate induces PD-L1+expression
on neutrophils via MCT1/NF-κB/COX-2 pathway, resulting in
inhibiting the efficacy of Lenvatinib. Thereby, it was believed that
the COX-2 inhibitor could reduce PD- L1+neutrophil and restore
T cell cytotoxicity (49). Lactate can impair T cell proliferation
by reducing stress independent of microenvironment acidification,
which depletes the GAPDH and PGDH responses of NAD+and
deprives proliferative T cells of glucose-derived serine. Manipulating
NAD redox metabolism may promote the differentiation and
activation of T cells and open a new way to selectively promote
immune regulation to enhance anti-tumor immunity (58).
GPR81 is expressed not only in cancer cells, but also in immune
cells such as dendritic cells and macrophages (119). Lactate can not
only affect cell proliferation, invasion, angiogenesis, and immune
tolerance by activating GPR81 on tumor cells but may also promote
tumor growth by activating GPR81 on non-tumor cells in the TME,
as there is a functional crosstalk between tumor cells and other
cells in the TME, making GPR81 a potential therapeutic target.
Targeting GPR81 could inhibit the growth of cancer cells and activate
the “enemy killing function” of the patient’s immune system to
fight the tumor. GPR81 was found closely related to tumorigenesis,
development, treatment, and prognosis in clinical trials, but still,
certain problems remain to be solved, such as the specific mechanism
of action is not fully understood, the safety and feasibility of
anti-GPR81 targeting therapy, and how to use it in clinical
trials. In vitro, silencing GPR81 can effectively eliminate GPR81-
induced angiogenesis (78). The discovery of small synthetic non-
metabolite ligands for structure-based metabolite receptors is rapidly
developing as many new GPCR structures are solved (120). With
the maturation of experimental techniques and further research,
it is believed that GPR81 will have good application prospects in
the future.
5. Conclusions and perspectives
Lactate was neglected for a long time in the field of oncological
research, but studies conducted over the past decades reveal that
it plays a significant role in the development and progression
of cancer by increasing angiogenesis, cancer cell migration, and
metastasis. By modulating lactate in the tumor microenvironment,
it was found that the GPR81 receptor inhibits host immune cells,
resulting in an advanced immunological evasion by tumor cells.
According to a number of research, the suppression of the anti-
cancer effect of several immune cells raised by lactate deposited
in the TME is transient. If extracellular lactate is depleted and
the microenvironmental pH is restored, it is possible to boost the
therapeutic efficacy of PD-1/PD-L1 therapeutics. Given the crucial
role that lactate plays, anti-glycolytic agents such as LDHA inhibitors
are capable of greatly limiting tumorigenesis. In fact, numerous
other anti-tumor immune cells also rely on glycolysis to exert
their functionality. Therefore, accordingly, it is assumed that anti-
glycolytic inhibitors that inhibit the proliferation of tumor cells would
reduce the anti-tumor immunological action of the host, rendering
the treatment far less effective. Most current glycolysis inhibitors
are inefficient, require high doses, and have varying degrees of
damage to the immune system. Therefore, there is an urgent need
to find highly effective and specific glycolytic inhibitors. Further
understanding of the metabolic differences between tumor cells and
immune cells is needed to identify new targeted agents that are more
effective and can more appropriately modulate the immune response
in vivo. Therapeutic regimens that target metabolism can potentially
be viable and revolutionary in the fight against cancer by combining
them with other therapeutic approaches such as immunotherapy
and chemotherapy.
Author contributions
ZZL, QW, XFH, and MTY designed this manuscript. ZZL,
QW, XFH, MTY, ZRL, and SJZ prepared and drafted the
manuscript. QW, XFH, ZRL, and SJZ prepared the figure.
ZZF, QC, HJH, LL, FF, QWW, YQW, and YDT enhanced the
language and analyzed the literature. AHG edited and revised
manuscript. All authors contributed to the article and approved the
submitted version.
Funding
This study was supported by Jiangsu Provincial Science and
Technology Department (Social Development)—Clinical Forward
Technology Project, BE2022778.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may
be made by its manufacturer, is not guaranteed or endorsed by the
publisher.
Frontiers in Nutrition 07 frontiersin.org
Li et al. 10.3389/fnut.2023.1113739
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