Lactate, once regarded as a metabolic waste product
of glycolysis, is now considered a multifunctional molecule that
promotes cancer progression. Notably, the Warburg effect is a
hallmark of cancer metabolism; even under oxygen-rich conditions,
tumor cells still preferentially metabolize glucose through
glycolysis and tend to ‘ferment’ glucose into lactic acid, leading
to an accumulation of lactic acid within the tumor microenvironment
(TME) (1). In addition to serving
a role in central carbon metabolism, lactate regulates tumor
immunity, antiviral responses and endoplasmic reticulum
(ER)-mitochondrial magnesium ion dynamics (2), and contributes to pathological
processes such as cancer progression (3). Lactate, as a signaling molecule,
regulates immune evasion, angiogenesis and therapeutic resistance
(4,5).
The discovery of lactylation, a lactate-derived
post-translational modification (PTM) of lysine residues, has
revealed a direct mechanistic link between glycolytic flux and
cellular regulation. Lactate, as the substrate for this
modification, catalyzes the addition of lactate groups to both
histone and non-histone proteins (6). This process links metabolic disorders
to epigenetic reprogramming, alterations in chromatin structure,
transcriptional programs and protein-protein interactions, thereby
promoting tumorigenesis (7). For
example, M1-polarized macrophages rely on aerobic glycolysis to
drive histone lactylation (8),
whereas B-cell adapter for PI3K facilitates their transition to a
reparative macrophage phenotype via lactylation (9). Lactate enhances the activity of
pyruvate kinase M2 (PKM2) by lactylating its K62 residues,
inhibiting the Warburg effect and promoting the transformation of
inflammatory macrophages (iNOS+ CD68+ cells)
into reparative macrophages (ARG1+ CD68+
positive cells) (10). In
non-small cell lung cancer (NSCLC), hypoxia-induced long noncoding
RNA-AC020978 amplifies glycolysis by promoting PKM2 nuclear
translocation and hypoxia-inducible factor-1α (HIF-1α) activation
(11). Furthermore, lactate
directly inhibits CD8+ T cells, natural killer T (NKT)
cells, dendritic cells and macrophages, while enhancing regulatory
T (Treg) cell stability and function, promoting immunosuppression
(12).
Researchers have also demonstrated the notable role
of lactylation in various types of cancer via numerous mechanisms
(Table I; Fig. 1). For example, pan-cancer analyses
have revealed upregulated lactylation-related genes (such as CREBBP
and EP300) and their association with kidney renal papillary cell
carcinoma and hepatocellular carcinoma (HCC) (13). Furthermore,
hypoxia-glycolysis-lactylation-related genes predict gastric cancer
(GC) progression (14), whereas
lactate-driven lactylation in colorectal cancer (CRC) is associated
with proliferation, metastasis and immune evasion (15). Lactylation serves a role in
tumorigenesis, including in tumor cell proliferation, invasion,
metastasis, DNA damage repair and immune cell killing, and also
promotes therapeutic resistance through autophagy activation, drug
efflux pumps and DNA damage repair (16).
The present review discusses the latest progress in
lactic acid biology, highlighting its dual role as a driving factor
in the pathogenesis of cancer and in therapeutic sensitivity. The
review also explores the impact of lactylation on metabolic
reprogramming, immune evasion and therapeutic resistance, and
discusses new strategies for precision oncology using this
pathway.
Lactylation critically regulates glycolytic flux in
cancer. Digestive system cancers account for >25% of global
cancer cases (17), with
lactylation emerging as a key regulator of immunosuppression and
metabolic reprogramming in the TME. Yang et al (18) identified 9,256 non-histone lysine
lactylation (Kla) sites in hepatitis B virus-associated HCC,
including adenylate kinase 2 lactylation at K28, which may drive
metastasis by disrupting metabolic regulation.
Abundant immune cell infiltration, particularly
macrophages, and increased genetic instability are traits
associated with high lactylation scores. Lactylation score can be
used to predict the malignant progression of GC and immune escape
(19). Hypoxia-induced
mitochondrial alanyl-tRNA synthetase AARS2 drives lactylation of
pyruvate dehydrogenase (PDH) complex components (PDHA1-K336 and
CPT2-K457/8), suppressing oxidative phosphorylation (OXPHOS) by
limiting pyruvate and acetyl-CoA influx (20). AARS1, upregulated in GC, catalyzes
lactate-AMP formation, promoting lactylation of p53 at lysine
120/139. This disrupts the DNA binding and transcriptional activity
of p53, coupling metabolic rewiring to proteomic changes that fuel
tumorigenesis (21). AARS1 also
activates the YAP-TEAD complex via nuclear lactylation, forming a
Hippo pathway feedback loop that accelerates GC progression and is
associated with poor prognosis (22). In addition, G-protein-coupled
receptor 37 (GPR37) activates the Hippo pathway, upregulating
lactate dehydrogenase A (LDHA) to enhance glycolysis and H3K18
lactylation (H3K18la). This promotes CXCL1/CXCL5 secretion,
remodeling the TME to favor metastasis. By contrast, GPR37
depletion suppresses the progression of liver metastasis in CRC
(23). Lactate also stabilizes
β-catenin via hypoxia-induced lactylation, activating Wnt signaling
and CRC proliferation (24).
Nucleolin lactylation promotes MAPK-activated death
domain protein translation and ERK activation, which is associated
with poor intrahepatic cholangiocarcinoma (iCCA) prognosis
(25). Non-histone lactylation
sites in oral squamous cell carcinoma (OSCC) cells, such as
hnRNPA1, SF3A1, hnRNPU and SLU7, are linked to glycolytic
dysregulation and tumorigenesis, highlighting the role of Kla in
pathogenesis (26). In lung
adenocarcinoma (LUAD), basic leucine zipper and W2 domains 2 (BZW2)
enhances glycolysis and isocitrate dehydrogenase 3 (IDH3G)
lactylation. Combined inhibition of BZW2 and glycolysis [such as
2-deoxy-D-glucose (2-DG)] suppresses tumor growth (27).
CircXRN2 is downregulated in bladder cancer (BCa)
tissues and suppresses tumor growth by binding to the speckle-type
POZ protein (SPOP) degron. This interaction blocks SPOP-mediated
degradation of large tumor suppressor kinase 1, activating the
Hippo signaling pathway to suppress tumor progression driven by
H3K18la (28). Upregulation of
zinc finger E-box binding homeobox 1 (ZEB1) in BCa is counteracted
by phosphofructokinase-1 (PFK-1), and PFK-1 inhibits glycolysis
through the lactylation of ZEB1 and suppresses its malignant
effects, including cell proliferation, migration and invasion
(29). During neuroendocrine
prostate cancer (NEPC) development, ZEB1 transcriptionally
regulates the expression of several key glycolytic enzymes, thereby
predisposing tumor cells to utilize glycolysis for energy
metabolism. Lactate accumulation enhances histone lactylation,
increasing chromatin accessibility and cellular plasticity
(including neural gene expression), thereby promoting NEPC
progression (30).
In BCa, the enhanced aerobic glycolysis rate
supports c-Myc expression through histone lactylation at the
promoter level. c-Myc further upregulates serine/arginine splicing
factor 10 (SRSF10) through transcription to drive the selective
splicing of MDM4 and Bcl-x in BCa cells. Restricting the activity
of key glycolytic enzymes may affect the c-Myc/SRSF10 axis to
reduce the proliferation of BCa cells (31). Potassium channel subfamily K member
1, which is upregulated in BCa, activates LDHA to enhance
glycolysis and H3K18la. LDHA upregulation creates a feed-forward
loop, reducing tumor cell adhesion and promoting
invasion/metastasis (32).
Deficiency in the Numb/Parkin pathway in prostate cancer (PCa) or
LUAD induces metabolic reprogramming, resulting in a significant
increase in the production of lactate acid, which subsequently
leads to the upregulation of histone lactylation and transcription
of neuroendocrine-associated genes (33). Aerobic glycolysis in anaplastic
thyroid cancer (ATC) increases overall protein lactylation by
increasing cellular lactate availability, and H4K12la activates the
expression of multiple genes necessary for ATC proliferation.
Furthermore, the oncogene BRAFV600E enhances glycolysis to
reprogram the cellular lactylation landscape, resulting in
H4K12la-driven gene transcription and cell cycle dysregulation.
Notably, treatment with a BRAFV600E inhibitor, combined with
blocking cell emulsification, can inhibit ATC progression in an
8505c xenograft tumor mouse model (34).
Autophagy and glycolysis are highly conserved
biological processes involving physiological and pathological
cellular activities. A number of core autophagy proteins undergo
lactylation during cancer (35).
Under nutrient deprivation, lactate-mediated lactylation of
autophagy proteins (such as VPS34, ULK1) enhances autophagic flux,
promoting tumor cell survival (36). In lung cancer and GC, lactate
mediates the lactylation of PIK3C3/VPS34 at lysine 356 and lysine
781 through acyltransferase KAT5/TIP60. The lactylation of
PIK3C3/VPS34 enhances the binding of PIK3C3/VPS34 to beclin 1,
ATG14 and UVRAG, increases the lipid kinase activity of
PIK3C3/VPS34, promotes macroautophagy/autophagy and advances the
endolysome degradation pathway (37).
In the TME, tumor cells export lactate via
monocarboxylate transporter 4 (MCT4), while oxidative tumor cells
import it through MCT1 to fuel OXPHOS (38). Although glycolysis dominates in
most types of cancer, OXPHOS remains active in malignancies such as
leukemia and lymphoma, enabling metabolic flexibility (39). Glucose fuels glycolysis, which
feeds into the TCA cycle and OXPHOS in oxidative cells, or sustains
lactate fermentation in hypoxic regions (40). In SW480 colon cancer cells,
lactylation targets glycolytic enzymes (such as PFKP-K688 and
ALDOA-K147), potentially establishing negative feedback loops to
modulate glycolysis (41). In
pancreatic adenocarcinoma cells, under glucose deprivation, lactate
enhances glutaminase 1-mediated glutamine metabolism and NMNAT1
lactylation, suppressing p38 MAPK and promoting survival (42). Solute carrier family 16 member 1
lactylation is critical for pancreatic ductal adenocarcinoma (PDAC)
progression, and targeting this axis may inhibit tumor growth
(43). In NSCLC, metabolic
dysregulation drives lactate accumulation, which replenishes the
TCA cycle while suppressing glucose uptake and glycolysis. Lactate
downregulates glycolytic enzymes [such as hexokinase (HK)-1 and
PKM] and upregulates TCA enzymes (including SDHA and IDH3G) via
histone lactylation at their promoters, enhancing NSCLC
proliferation and migration (44).
The hypoxic microenvironment resulting from reduced
local blood flow in pancreatic cancer (PC) triggers a shift in
glycolytic-dependent energy metabolism by stabilizing HIF-1α
(51). Elevated H3K18la in PDAC
activates TTK and BUB1B transcription, upregulating P300 to enhance
glycolysis. TTK phosphorylates LDHA at Y239, amplifying lactate and
H3K18la levels (52). Nuclear and
spindle-associated protein 1 (NUSAP1) binds c-Myc and HIF-1α to
upregulate LDHA. Lactate stabilizes NUSAP1 via Kla, forming a
feed-forward loop (NUSAP1-LDHA-lactate-NUSAP1) that drives
metastasis (53). In esophageal
cancer (EC), hypoxia not only enhances the expression of serine
hydroxymethyltransferase 2 (SHMT2) protein but also initiates the
lactylation of SHMT2 protein and enhances its stability, thus
accelerating the malignant progression of EC (54).
Angiogenic mimicry provides tumor cells with a blood
supply independent of endothelial cells (55). MAPK 6 pseudogene 4 stabilizes
Krüppel-like factor 15, which transcriptionally activates LDHA.
LDHA-mediated lactylation of vascular endothelial growth factor
receptor 2 (VEGFR2) and VE-cadherin enhances their expression,
fostering GBM cell proliferation, migration and angiogenic mimicry.
However, the specific lactylation sites in VEGFR2 and VE-cadherin
involved in GBM still require further exploration (56). FK506-binding protein 10 (FKBP10)
binds LDHA, enhancing LDHA-Y10 phosphorylation to amplify the
Warburg effect and histone lactylation. By contrast, HIF-2α, a
driver of angiogenesis and redox balance, suppresses FKBP10
transcription. Combining HIF-2α inhibitors (such as PT2385) with
FKBP10 targeting enhances antitumor efficacy, particularly in
low-FKBP10 ccRCC (57). Lactate
import via MCT1 stabilizes HIF-1α under normoxia through HIF-1α
lactylation, perpetuating KIAA1199 expression. By contrast,
silencing KIAA1199 restores 3A semaphoring (sema)3A and inhibits
angiogenesis (58). Lactate also
stabilizes HIF-1α, promoting discoidin, CUB, and LCCL
domain-containing protein 1 (DCBLD1) transcription. DCBLD1-K172
lactylation inhibits ubiquitination, blocking autophagy-mediated
degradation of G6PD to fuel the pentose phosphate pathway (PPP).
This activates the PPP, fueling cervical cancer cell migration,
invasion and growth (59).
G6PD K45 is lactylated during G6PD-mediated
antioxidant stress. In primary human keratinocytes and HPV-negative
cervical cancer C33A cell lines ectopically expressing HPV16 E6,
G6PD K45A is not lactylated, and the transduction of G6PD K45A has
been shown to increase the levels of glutathione and NADPH, and can
accordingly decrease the levels of reactive oxygen species. In
vivo, 6-aminonicotinamide inhibits the activity of the G6PD
enzyme or the re-expression of G6PD K45T, thereby suppressing tumor
proliferation (60). The
non-metabolizable glucose analog 2-DG and oxamate treatment have
been reported to decrease the levels of lactylation to inhibit
proliferation and migration, induce apoptosis and arrest the cell
cycle of EC cells. In addition, a study on EC xenograft tumor model
mice and EC cells confirmed that H3K18la may upregulate the
deubiquitinase ubiquitin-specific protease (USP)39, stabilizing
phosphoglycerate kinase 1 to activate the PI3K/AKT/HIF-1α axis and
to enhance glycolysis (61).
Lactylation orchestrates the progression of cancer
through extensive epigenetic reprogramming, modulating both histone
and non-histone targets to alter gene expression, RNA processing
and cellular phenotypes.
Histone lactylation directly modulates chromatin
dynamics. In GC, H3K18la activates vascular cell adhesion molecule
1, promoting GC cell proliferation and migration via AKT/mTOR
signaling, and recruits immunosuppressive mesenchymal stem cells
through CXCL1 upregulation, thereby promoting immune suppression
and tumor metastasis (62). In
CRC, tumor-derived lactate inhibits retinoic acid receptor γ in
macrophages, elevating H3K18la and IL-6/STAT3 signaling to polarize
macrophages toward a pro-tumorigenic state (63). Histone lactylation (such as H4K8la,
H4K16la) is suppressed by liver kinase B1, which induces senescence
by inhibiting telomerase reverse transcriptase (64). Furthermore, lactate in the TME of
LUAD reduces the transcription of solute carrier family 25, member
29 (SLC25A29) in endothelial cells. Specifically, the increase of
H3K14la and H3K18la in the SLC25A29 promoter region reduces the
transcription of SLC25A29, which affects the proliferation,
migration and apoptosis of endothelial cells (65). The NF-κB pathway promotes the
Warburg effect, thereby inducing the lactylation of H3 histone and
increasing the expression of LINC01127. The enhanced expression of
LINC01127 promotes the self-renewal of GBM cells and directly
guides POLR2A to the MAP4K4 promoter region to regulate the
expression of MAP4K4, thereby activating the JNK pathway and
ultimately regulating the self-renewal of GBM cells (66). Inactivation of the von
Hippel-Lindau (VHL) tumor suppressor triggers histone lactylation,
activating platelet-derived growth factor receptor β (PDGFRβ)
transcription; PDGFRβ signaling reciprocally enhances histone
lactylation, creating an oncogenic feedback loop (67).
The lactylation and delactylation of non-histone
proteins are closely related to the pathogenesis of HCC. Sirtuin
(SIRT)3 deficiency in HCC permits the accumulation of cyclin
(CCN)E2 lactylation, whereas honokiol-mediated SIRT3 reactivation
delactylates CCNE2-K348 to suppress HCC cell proliferation
(68). Furthermore, CENPA-K124
lactylation enhances the interaction between CENPA and the
transcription factor YY1, driving CCND1 and neuropilin 2 expression
to promote HCC progression (69).
In CRC, KAT8-catalyzed lactylation of eEF1A2K408 has been shown to
result in boosted translation elongation and enhanced protein
synthesis, which contribute to tumorigenesis (70). Furthermore, H3K18la has been
reported to increase METTL3 expression in tumor-infiltrating
myeloid cells. Notably, METTL3 mediates m6A modification on Jak1
mRNA in tumor-infiltrating myeloid cells, and the m6A-YTHDF1 axis
enhances JAK1 protein translation efficiency, subsequent
phosphorylation of STAT3 and immunosuppression (71). In ocular melanoma, histone
lactylation promotes tumorigenesis by increasing the expression of
YTHDF2. YTHDF2 recognizes m6A-modified PER1 and TP53 mRNA, promotes
their degradation and accelerates the occurrence of ocular melanoma
(72). Histone lactylation
enhances the expression of AlkB homolog 3 (ALKBH3) by removing the
m1A methylation of SP100A. ALKBH3 lactylation facilitates
promyelocytic leukemia protein nuclear condensate formation,
bridging m1A modification to metabolic reprogramming (73). Elevated NOP2/Sun RNA
methyltransferase family member 2 (NSUN2), an m5C
methyltransferase, and Y-box binding protein 1 (YBX1), an m5C
methylation recognition enzyme, drive m5C modification of ENO1 mRNA
in CRC, promoting lactate production. This lactate then induces
NSUN2 expression via histone H3K18 lactylation and enhances RNA
binding of NSUN2 through its own lactylation (K356), creating a
feed-forward loop linking metabolism and epigenetics (74). Furthermore, the chemotherapeutic
agent gemcitabine (GEM) increases histone acetylation but reduces
histone lactylation, suggesting cross-talk between PTMs in the
mechanism of GEM (75). These
mechanisms collectively establish lactylation as a master regulator
of cancer epigenetics, influencing angiogenesis, therapy resistance
and metabolic adaptation.
Lactylation orchestrates immunosuppression within
the TME by reprogramming immune cell function and recruitment. In
HCC, dysregulation of histone acetyltransferase EP300 and histone
deacetylase (HDAC)1-3 alters immune cell infiltration (including B
cells) and predicts poor prognosis when HDAC1/2 are upregulated
(76). Glucose transporter 3
(GLUT3) levels are significantly increased in GC tissues. By
contrast, after knocking down GLUT3, the levels of LDHA,
L-lactylation, H3K9, H3K18 and H3K56 are markedly reduced. Notably,
in GLUT3-knockdown cell lines, upregulation of LDHA reverses the
lactylation and epithelial-mesenchymal transition functional
phenotypes, while Kla is enriched in GC tissues and predicts poor
survival, underscoring its role as a prognostic biomarker (77,78).
Claudin-9 promotes glycolytic metabolism in GC cells by activating
the PI3K/AKT/HIF-1α signaling pathway, resulting in increased
lactate production. Lactate, as a glycolytic metabolite, can
enhance the lactylation of programmed death ligand 1 (PD-L1) and
improve its stability. This modified PD-L1 will inhibit the
antitumor immune response of CD8+ T cells, thereby
enhancing GC cell immune evasion and promoting the progression of
GC (79). STAT5-induced lactate
accumulation promotes nuclear translocation of E3 binding protein,
increases lactylation of the PD-L1 promoter, and subsequently
induces PD-L1 transcription, driving immunosuppression in acute
myeloid leukemia (80).
The gut microbiome further amplifies
immunosuppression through lactylation. In CRC, RIG-I lactylation
induced by Escherichia coli inhibits the recruitment of
NF-κB to the NLRP3 promoter, suppresses inflammasome activity,
impairs CD8+ T-cell function and simultaneously enhances
Treg cell-mediated tolerance (81). Similarly, gram-negative bacterial
lipopolysaccharide upregulates the expression of LINC00152 and
promotes the invasion of CRC cells by introducing histone
lactylation on its promoter, reducing the binding efficiency of
inhibitory factor YY1 to it (82).
In lung squamous cell carcinoma, solute carrier
family 2 member 1 (SLC2A1) upregulation is associated with elevated
protein lactylation and SPP1+ macrophage abundance,
driving therapy resistance (83).
In advanced GBM, monocyte-derived macrophages dominate the TME and
secrete IL-10 via PERK-driven histone lactylation, inhibiting
T-cell activity. PERK deletion abolishes lactylation, restores
T-cell function and delays tumor growth (84). Furthermore, single-cell RNA
sequencing has confirmed lactylation-related gene expression across
glioma-infiltrating immune cells (monocytes, macrophages,
CD8+ T cells), and lactylation scores have been reported
to be associated with lipogenesis, DNA repair and mTORC1 signaling
(85). HK-3 indirectly affects
neuroblastoma progression by recruiting and polarizing M2-like
macrophages through the PI3K/AKT/CXCL14 axis. After knocking down
the expression of HK3, the levels of histone lysine lactylation in
neuroblastoma cell lines SK-N-SH and SK-N-BE (2) are significantly reduced, and the
lactate concentration in the supernatant of SK-N-SH/SK-N-BE
(2) cell cultures is significantly
reduced. These findings indicate that in neuroblastoma HK3 affects
lactate secretion in the microenvironment and regulates histone
lactylation (86). In the TME of
malignant pleural effusion (MPE), the antitumor activity of
CD8+ T cells and NKT-like cells is inhibited, and the
function of Treg cells is enhanced. The glycolytic pathway and
pyruvate metabolism are highly activated in a distinct
subpopulation of NKT-like cells expressing FOXP3 in MPE. Notably, a
small molecule inhibitor of MCT1, 7ACC2, has been shown to reduce
FOXP3 expression and histone lactylation levels in NKT-like cells
(87).
In addition to regulating metabolic reprogramming,
and epigenetic and immune pathways, lactylation drives
multi-faceted treatment resistance in cancer. Previous proteomic
profiling identified 1,438 lactylation sites across 772 proteins in
HCC tissues, implicating lactylation in amino acid metabolism,
ribosomal function and fatty acid metabolism (88). Lactylation of USP14 and ATP-binding
cassette (ABC) subfamily F member 1 is associated with drug
sensitivity. Notably, patients with high-risk HCC respond better to
sorafenib, whereas low-risk patients exhibit elevated Tumor Immune
Dysfunction and Exclusion scores and benefit from immunotherapy
(89). Lactylation also activates
oncogenic pathways (Wnt, MAPK, mTOR, NOTCH) via nuclear receptor
6A1, oxysterol-binding protein 2 and UNC119B, linking Kla to immune
evasion and therapy resistance (90). Apicidin treatment reduces
lactylation, suppressing HCC migration and proliferation, although
clinical validation and mechanistic crosstalk with other PTMs
require further study (91).
In GC, copper stress lactylates METTL16 at K229,
enhancing copper ionophore (elesclomol) efficacy. Combining
elesclomol with the SIRT2 inhibitor AGK2 amplifies copper toxicity,
suggesting a therapeutic strategy to overcome chemoresistance
(92,93). In CRC, H3K18la upregulation in
bevacizumab-resistant tumors, which upregulates autophagy protein
RUBCNL/Pacer through BECN1 interaction, enhances autophagosome
maturation and survival (94). In
diapause-like CRC, SMC4 and phosphoglycerate mutase 1 loss disrupts
F-actin assembly and upregulates ABC transporters via histone
lactylation, reducing chemotherapy sensitivity (95). Aldolase B-activated PDH kinase 1
drives lactylation of circulating carcinoembryonic antigen,
activating CEACAM6 to promote proliferation and chemoresistance in
CRC (96).
Hypoxia in the TME amplifies lactate production,
global lactylation and immunosuppression (97,98).
Hypoxia upregulates SOX9 lactylation, enhancing stemness and
invasion in NSCLC (99). AKR1B10
promotes LDHA-driven lactate accumulation, stimulating H4K12la to
activate CCNB1 and accelerate DNA replication, conferring
pemetrexed resistance in lung cancer brain metastasis (100). This aligns with findings that
tumor resistance stems from heterogeneity and immunosuppressive TME
interactions (101).
In BCa, H3K18la drives the key transcription factors
YBX1 and YY1 associated with cisplatin resistance, thereby
promoting cisplatin resistance (102). Sema3A suppresses VEGFA-induced
colony formation, proliferation and PD-L1 expression in PCa.
Sema3A, along with sema3B/C/E, predicts biochemical recurrence in
low- to intermediate-risk PCa post-prostatectomy (103). Prognostic models combining the
lactylation-related genes ALDOA, DDX39A, H2AX, KIF2C and RACGAP1
has been shown to predict disease-free survival and treatment
response in PCa. These genes are highly expressed in
castration-resistant tumors, underscoring the clinical relevance of
lactylation (104). In
PTEN-deficient metastatic castration-resistant PCa, a PI3K
inhibitor (PI3Ki) has been reported to reduce histone lactylation
within tumor-associated macrophages (TAMs), resulting in their
anticancer phagocytic activation, which is augmented by ADT/aPD-1
treatment and abrogated by feedback activation of the Wnt/β-catenin
pathway. Furthermore, co-targeting Wnt/β-catenin signaling with
LGK-974 in combination with PI3Ki, has previously demonstrated
durable tumor control in 100% of mice via H3K18lac suppression and
complete TAM activation (105,106). Gambogic acid disrupts this cycle
by recruiting SIRT1 to delactylate chaperone protein CNPY3,
inducing lysosomal rupture and pyroptotic cell death (107). Lactylation-related genes
influence BCa growth, immune microenvironment remodeling and
therapy resistance by modulating lactate transport within the TME
(108). In addition, H4K12la
contributes to chemoresistance and adverse immune responses in
breast cancer (109).
Lactylation modulation represents an emerging
frontier for targeted cancer therapy, with implications for
treatment response prediction and combination strategies. Yu et
al (110) identified 14
lactylation-related genes in ovarian cancer (OC) using The Cancer
Genome Atlas database, stratifying patients into low- and high-risk
groups. The low-risk profile was associated with metabolic
processes (thermogenesis and OXPHOS) and immune responses
(neutrophil extracellular traps and IL-17 signaling). High-risk
features were associated with cell adhesion (proteoglycans and
adhesive plaques) and carcinogenic signaling (Wnt and extracellular
matrix-receptor interactions). Notably, lactylation-related genes
were shown to be closely related to tumor classification and
immunity, and OC based on lactylation-related characteristics was
indicated to have a good prognostic performance.
Similarly, in skin cutaneous melanoma (CM),
Kaplan-Meier survival analysis revealed that the lactylation
low/TME high group had the highest overall survival (OS) rate,
whereas the lactylation high/TME low group had the lowest OS rate.
In addition, CM immunotherapy was revealed to be more suitable for
patients in the lactylation low/TME high group (111). Notably, calmodulin-like protein 5
is a core lactylation-associated gene in CM, which is associated
with patient survival and immune infiltration (112).
Lactate accumulation in the TME promotes immune
evasion and tumor survival, but lactylation also offers therapeutic
opportunities. Preclinical studies have highlighted strategies such
as inhibiting lactate production (for example, via LDHA inhibitors)
or disrupting histone lactylation [such as with demethylzeylasteral
(DML), royal jelly acid (RJA) or fargesin] to reduce tumor energy
supply or enhance immunotherapy efficacy (Fig. 2). However, these findings are
limited by preclinical risks, as results from homogeneous mouse
models may overestimate efficacy in humans, where TME heterogeneity
remains unresolved.
In a mouse liver cancer cell model (Hepa1-6), LDHA
inhibitors have been shown to suppress the immunoregulatory effects
of Treg cells in the TME by reducing lactate concentration.
Notably, combined treatment with anti-PD-1 and LDHA inhibitors has
a stronger antitumor effect than anti-PD-1 alone (118). The anti-epileptic drug,
stiripentol enhances the sensitivity of cancer cells to
temozolomide by inhibiting lactylation. Lactylation is upregulated
in relapsed GBM tissues and temozolomide-resistant cells, mainly
since H3K9la confers temozolomide resistance in GBM through
Luc7L2-mediated intron-7 retention of MLH1. Stiripentol enhances
temozolomide sensitivity in GBM by inhibiting LDH activity and
H3K9la-mediated resistance (119). Oxamate promotes immune activation
of chimeric antigen receptor (CAR)-T cells infiltrating tumors. In
a GBM mouse model, oxamate has been shown to promote the immune
activation of tumor-infiltrating CAR-T cells through altering the
phenotypes of immune molecules and increasing Treg-cell
infiltration (120). However,
murine models cannot fully recapitulate human metabolic plasticity.
PD-1/PD-L1 is a major inhibitory checkpoint pathway that regulates
immune escape in patients with cancer, and its participation and
inhibition notably reshape the pattern of tumor clearance. Immune
checkpoint inhibition targeting PD-1/PD-L1 is a reliable tumor
therapy (121). Notably, lactate
treatment in PCa cells can increase the expression of HIF-1α and
PD-L1, while restricting the expression of sema3A, whereas
silencing the expression of MCT4 reverses this process. Evodiamine
blocks lactate-induced angiogenesis by restricting the histone
lactylation and expression of HIF-1α in PCa, further enhances
Sema3A transcription, inhibits PD-L1 transcription, and induces
ferroptosis by decreasing the expression of low GSH peroxidase 4
(122).
Proteomics analysis has shown that H4K12la is
elevated in triple-negative breast cancer (TNBC) tissues, and
H4K12la has been shown to be positively associated with the
proliferative marker Ki-67 and negatively associated with OS rate
(123). However, it is still
necessary to validate H4K12la as a biomarker for TNBC
resistance.
While lactylation is a promising therapeutic target,
integrating preclinical findings with clinical practice requires:
i) Interdisciplinary collaboration; for example, integrating
metabolomics, epigenetics and immunology to address the complexity
of the underlying mechanism. ii) Robust clinical validation, with
staged trials to evaluate safety, efficacy and related biomarkers.
iii) A patient-centered approach to develop guidelines for targeted
lactylation therapy based on tumor subtypes, TME background and
metabolic vulnerability. By addressing these challenges, lactate
regulation could become a cornerstone of precision oncology.
Tumor cells produce lactate through glycolysis,
resulting in local acidification and altering the pH value of the
TME. The acidified environment affects the cellular components of
the TME, and affects tumor growth and spread. Lactate acts as a
signaling molecule to regulate tumor growth, invasion, metastasis
and therapeutic response. Furthermore, lactylation is involved in
critical biological processes such as glycolytic cell function,
macrophage polarization, angiogenesis, mitochondrial activity and
nervous system regulation. Lactylation also modulates tumor
behavior by influencing signal transduction pathways. The interplay
between lactylation and the immune cycle is complex, involving
metabolism, immune cell function, inflammatory responses and immune
regulation (Fig. 3). Therefore,
intervening in lactylation may be a new target for tumor
therapy.
The structural complexity and functional diversity
of histones necessitate further exploration of their lactylation in
cancer to elucidate its role and mechanism in tumor development.
H3K18la is associated with shifts in cellular states, with
quantitative lactylation changes at promoters and enhancers
potentially driving these transitions (124). H3K9la levels are upregulated in
endothelial cells in response to VEGF stimulation, and
hyperlactylation of H3K9 inhibits expression of the lactylation
eraser HDAC2, whereas upregulation of HDAC2 decreases H3K9la and
suppresses angiogenesis (125,126). Elevated H3K9la levels in LCSCs,
HCC and GBM are associated with tumorigenicity, drug resistance and
immunosuppression (127). Histone
lactylation thus influences gene expression, tumor progression and
immune evasion, underscoring the need to determine its underlying
mechanisms for developing novel therapies.
In GC, lactate-driven lactylation of NBS1 promotes
homologous recombination (HR)-mediated DNA repair, fostering
chemoresistance, while inhibition of lactate production has emerged
as a promising strategy (128).
Similarly, MRE11 lactylation at K673, mediated by cyclic-AMP
response binding protein-binding protein (CBP), enhances HR repair,
whereas targeting CBP or LDH sensitizes tumors to chemotherapy in
preclinical models (129).
KRAS-driven lactylation activates circATXN7, which sequesters NF-κB
p65 in the cytoplasm, promoting immune evasion (130). However, the potential for
resistance to lactylation-targeted therapies remains a concern, as
tumors may exploit alternative DNA repair pathways or upregulate
compensatory PTMs, highlighting the need for combination
therapies.
While preclinical studies have demonstrated the
potential of lactylation inhibition (such as by targeting LDH or
CBP) to enhance chemosensitivity and reduce immune evasion,
clinical translation faces notable hurdles (131,132). Small molecule inhibitors and
antibodies targeting lactylation-related proteins have shown
promising prospects in preclinical models, and targeted lactylation
is expected to improve the immunosuppressive TME. For example, it
has been shown that activating the SIRT3 lactase function can
restore the anti-leukemia activity of NK cells (133). In addition, irinotecan has been
found to possess new functions of inhibiting lactylation. Their
safety is known and they can enter clinical trials more quickly
(134). A number of
small-molecule inhibitors also exhibit synergistic effects when
used in combination with existing chemotherapy drugs or
immunotherapies. Furthermore, lactylation levels vary among
different tumor types and individuals Therefore, specific
lactylation sites may be considered new and effective targets for
tumor diagnosis and treatment. Furthermore, developing highly
specific inhibitors that can precisely target specific lactylated
proteins or sites is currently a challenge, and it is necessary to
avoid interfering with other similar post-translational
modifications (such as acetylation). How to efficiently deliver
drugs to tumor tissues and penetrate into the interior of tumor
cells is a common problem faced by clinical application. New
delivery systems such as nano-strategies may be the solution. In
addition, the lactylation regulatory network is complex, and tumor
cells may develop drug resistance through other compensatory
pathways; thus, it is necessary to continuously explore the
mechanism and develop combined strategies (135,136).
Lactylation detection remains technically
challenging. While high-performance LC-MS/MS, LC/MS and anti-Kla
immunoblotting are widely used, improved precision is needed to
distinguish lactylation from other PTMs, particularly given the
overlapping molecular weights of histones H1, H3 and H4 (114). Advanced proteomics analysis and
site-specific antibodies could address these limitations.
Clinically, interventions must account for tissue-specific oxygen
gradients and lactylation heterogeneity. Although lactylation
biomarkers could monitor therapeutic response, validation in human
cohorts is lacking. Early-phase trials of lactylation inhibitors
are needed to assess safety, efficacy and optimal dosing.
As understanding of the role of lactylation in tumor
biology deepens, targeting this pathway is expected to address
treatment resistance and immunosuppression in some of the most
aggressive malignant tumors, especially those driven by glycolytic
metabolism and immune rejection. Future success will depend on a
careful balance of efficacy and toxicity, the intelligent design of
combination regimens, and the development of diagnostic tools to
identify patients most likely to benefit from lactylation-directed
therapy.
Not applicable.
This work was supported by Research Funds of Center for Xin'an
Medicine and Modernization of Traditional Chinese Medicine of
institute of Health and Medicine, Hefei Comprehensive National
Science Center (grant no. 2023CXMMTCM025), the Anhui Education
Department (grant no. gxgwfx2022019), the Anhui University of
Chinese Medicine (grant no. 2022BHTNXA05, DT2400001288) and the
Anhui Administration of Traditional Chinese Medicine (grant no.
2022CCYB10).
Not applicable.
XW, JC and BW collected and reviewed the literature,
and wrote the review. YL, XZ and YS collected and reviewed the
literature. CM made substantial contributions to the conception and
design of the work. YH is responsible for the design of this work,
the final approval of the version to be published, and for all
aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately
investigated and resolved. Data authentication is not applicable.
All authors read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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