In 2020, colorectal cancer (CRC) is the third most
prevalent malignancy globally and the second leading cause of
cancer-associated deaths (1)
Distant metastasis is a key driver of mortality in CRC, with the
liver being the most common site of metastasis (2). A total of 15–25% of patients with CRC
present with synchronous liver metastases at initial diagnosis,
while a further 15–25% develop metachronous liver metastases
following primary CRC resection (2). Currently, a limited number of these
liver metastases are amenable to surgical resection, and the 5-year
survival rate for these patients is 25–44%. Moreover, up to 60% of
patients experience rapid recurrence following resection (3).
The exact mechanisms underlying colorectal liver
metastasis (CRLM) remain poorly understood. Tumor cell
dissemination from the primary site to distant organs and the
subsequent formation of metastatic tumors involve a dynamic process
regulated by numerous genes and signaling pathways. This process
includes tumor cell detachment from the primary site, entry into
the circulatory or lymphatic system, extravasation and colonization
at secondary sites. Tumor cell invasion, migration, adhesion,
extracellular matrix remodeling, neovascularization and immune
regulation are key in facilitating this metastatic cascade. The
rise of immunotherapy, with its notable clinical success, has
highlighted the critical role of the tumor immune microenvironment
(TIME) in CRLM. CRLM represents a complex interaction between tumor
and microenvironmental cells. Tumor cells, while acquiring invasive
phenotypes, maintain intercellular communication with
microenvironmental cells, regulating their functions through both
direct and indirect mechanisms. This regulation involves the
expression of immune checkpoint molecules and the secretion of
cytokines, establishing a microenvironment conducive to tumor cell
colonization and proliferation (4).
Moreover, suppressive immune cells enhance the invasiveness of
tumor cells by activating pro-metastatic signaling pathways. This
interaction between tumor cells and the microenvironment drives the
development of CRLM (Fig. 1).
The development, invasion and metastasis of CRC are
complex biological processes involving multiple genetic
alterations. Successive mutations and abnormal expression of genes
such as APC, KRAS, BRAF and PTEN activate signaling pathways
promoting CRC invasion and metastasis (5).
Epithelial-mesenchymal transition (EMT) is a
critical precursor to CRLM. EMT refers to the phenotypical
transformation of tumor epithelial cells into a mesenchymal
phenotype, which enhances their migratory capacity (6). This involves the loss of intercellular
junctions, increased secretion of intercellular plasma hydrolases
and disruption of apical polarity, resulting in a breakdown of
cell-cell adhesion. Concurrently, these changes induce the
expression of N-cadherin, vimentin and α-smooth muscle actin,
facilitating the transition from polarized epithelial cells to
multipolar mesenchymal cells. This transformation increases cell
motility, enabling tumor cells to detach from epithelial clusters
and migrate individually in a mesenchymal manner, further enhancing
the metastatic potential (7). The
E-cadherin-β-catenin complex serves a pivotal role in maintaining
epithelial integrity. Disruption of this complex leads to the
detachment of cells from the primary tumor, enabling invasion and
migration through the extracellular matrix and entry into the
circulatory or lymphatic system. This is an important initiating
step in the development of CRLM (8).
The acquisition of an invasive phenotype in CRC is
governed by signaling pathways, including Wnt/β-catenin (9,10),
TGF-β (11,12), PI3K/AKT (13–15),
MEK/ERK (16,17) and hepatocyte growth factor (HGF)/MET
(18). These pathways are regulated
by intracellular oncogenes and tumor suppressor genes, as well as
tumor microenvironmental signaling factors that influence tumor
cell invasion and metastasis (Fig.
2).
Hepatic susceptibility to colonization by
circulating tumor cells compared with other metastasis sites such
as the lungs and peritoneum is primarily attributed to its highly
permeable blood vessels, unique hemodynamic properties and distinct
immune microenvironment. Notably, the ability to tolerate immune
responses contributes to the creation of an immunosuppressive
microenvironment, which protects the organ from excessive immune
reactions to antigens. Additionally, liver homeostasis is
maintained by specialized resident cells and diverse immune cell
populations, which collectively regulate immune responses and
oncogenesis (19–21).
During liver metastasis, immune cells undergo
functional changes as a result of communication with tumor cells.
Typically, under the influence of tumor cells, immune cells shift
toward an immunosuppressive phenotype. Simultaneously, these immune
cells reverse their roles to promote the invasive behavior of tumor
cells by releasing pro-metastatic cytokines. This facilitates the
establishment of a pre-metastatic niche, supporting the
colonization of metastatic tumor cells and leading to the formation
of metastatic foci (Fig. 3)
(22).
Regulatory T cells (Tregs), identified by the
expression of CD25 and FoxP3, are classical immune suppressors
(38). In CRLM, Tregs are the
primary source of IL-10, which increases PD-L1 expression on
monocytes. This interaction diminishes CD8+ T cell
infiltration and impairs antitumor immunity in CRLM (39). Previous studies have shown a
significant increase in the proportion of Tregs in both mouse
models (39,40) and resected CRLM specimens from
patients (41). Furthermore,
Treg-mediated suppression of the antitumor immune response is
linked to clinical prognosis of patients with CRLM (42). Studies have revealed a paradox where
elevated infiltration of FOXP3+ T cells in CRC is
associated with improved relapse-free and disease-specific
survival, while low FOXP3+ T cell infiltration is
associated with poor prognosis (31,43).
This discrepancy may be due to the heterogeneity of Tregs within
the tumor microenvironment (TME). Saito et al (44) identified two distinct subpopulations
of Tregs in CRC terminally differentiated immunosuppressive
FoxP3high and pro-inflammatory FoxP3low
subtypes. Inflammatory Treg-infiltrating CRC showed significant
upregulation of genes associated with inflammation and immune
responses. Functionally distinct subpopulations of Tregs influence
CRC prognosis in opposing directions, with high FOXP3 expression in
immunosuppressive Treg-infiltrating tumors associated with poorer
outcomes. Pedroza-Gonzalez et al (45) demonstrated that, compared with Tregs
from primary hepatocellular carcinoma, Tregs in CRLM exhibit higher
expression of glucocorticoid-induced tumor necrosis factor receptor
and stronger immunosuppressive activity. These findings suggest
that a more precise characterization of Treg subpopulations in CRC
and its liver metastases may deepen the understanding of Treg
function in CRLM and help refine therapeutic strategies.
Macrophages within the TME exhibit notable
plasticity and heterogeneity, classified into M1-type macrophages
with pro-inflammatory, immune activating and antitumor properties,
and M2-type macrophages, which possess immunosuppressive and
pro-tumor functions. M2 macrophages are the dominant subtype in
liver metastases (46,47) and associated with poor prognosis
(48).
M2 macrophages facilitate tumor invasion and
metastasis through several mechanisms, such as remodeling the
extracellular matrix (49) and
inducing EMT (50,51). Additionally, M2 macrophages
contribute to tumor angiogenesis through the secretion of VEGF
(52) and support immune evasion by
releasing immunosuppressive cytokines such as IL-10 and TGF-β
(53). Aberrant expression and
activation of signaling molecules such as X-box binding protein 1
(XBP1) in M2 macrophages are further amplified by elevated cytokine
secretion of cytokines, including IL-6 and VEGFA, which accelerate
CRLM progression (54).
Cytokines and exosomes serve pivotal roles in CRC
cells by inducing macrophage polarization toward the M2 phenotype.
TGF-β, a classical cytokine, regulates macrophage polarization and,
in CRLM, is modulated by pro-oncogenic factors such as collagen
triple helix repeat containing 1, which further promotes CRLM by
remodeling infiltrating macrophages via TGF-β signaling (55). Additionally, CCL2 is a key regulator
of M2-type polarization, which fosters CRLM progression.
Pro-oncogenic factors such as STAT3, transcription factor 4 (TCF4)
and spondin 2 in CRC cells stimulate CCL2 secretion (56–58).
Targeting the CCL2/CCR2 chemokine pathway reduces
M2-typetumor-associated macrophages (TAMs) at metastatic sites,
disrupts the immunosuppressive TME and enhances the susceptibility
of mCRC to antitumor T cell responses (59). Tumor-derived factors such as CCL20,
IL-10, VEGF and IL-1β also serve key roles in promoting macrophage
infiltration and M2 polarization in CRLM (60,61).
Exosome-mediated release of pro-oncogenic factors also contributes
to the M2 polarization. CRC cells induce M2 polarization and
establish an immunosuppressive pre-metastatic niche via the
exosomal release of microRNAs (miRs; such as miR-25-3p, miR-130b-3p
and miR-425-5p, miR-21-5p, miR-203, miR-934, miR-135a-5p and
miR-106a-5p) and signaling molecules such as heat shock protein
90B1, and circ-0034880, which promote CRLM (62–69).
Neutrophils in the TME exhibit dual roles: In
early-stage tumors, they enhance T cell responses, while in
advanced tumors, they adopt an immunosuppressive function (72). Similarly to macrophages, neutrophils
in the TME can differentiate into distinct subsets, categorized as
antitumor N1- and pro-tumor N2-type (73). N1-type neutrophils enhance tumor
cell killing by expressing immune-activating cytokines and
chemokines while inhibiting arginase expression. TGF-β in the TME
induces the polarization of neutrophils from N1 to N2-type. N2-type
neutrophils suppress tumor-killing T cell activity (74) and promote tumor invasion and
metastasis by stimulating angiogenesis (75).
Tumor cells induce neutrophil infiltration via
multiple pathways. CRC cells secrete granulocyte colony stimulating
factor, which recruits neutrophils and upregulates Bv8/Prokineticin
2 expression, promoting immunosuppression and angiogenesis, thereby
contributing to CRC metastasis (75,79).
Seubert et al (80)
demonstrated that tumor-derived tissue inhibitor of
metalloproteinases 1(TIMP-1) upregulates stromal derived factor-1,
recruiting neutrophils to the liver, and promoting liver
metastasis. Aberrantly expressed molecules such as cell migration
inducing hyaluronidase 1 (81) and
DNA rrimase subunit 1 (82) in CRLM
ead to the production of CXCL1 and CXCL3, causing accumulation of
immunosuppressive neutrophils, ultimately enhancing CRLM
progression. These findings suggest potential therapeutic targets
for future CRLM research and treatment.
MDSCs, a heterogeneous group of immature myeloid
cells, serve a pivotal role in facilitating CRLM by inducing
immunosuppression, remodeling the extracellular matrix and
promoting angiogenesis (83).
Additionally, MDSCs are involved in the formation of NETs within
the pre-metastatic niche (84).
Abnormal expression and secretion of cytokines trigger MDSC
infiltration, further advancing CRLM. CCL2-CCR2 signaling has been
shown to induce MDSC infiltration in a STAT3-dependent manner,
enhancing their immunosuppressive functions and contributing to CRC
progression (85–87). Furthermore, CRC-derived CCL15
(88) and TME-derived CXCL1
(89,90) recruit MDSCs to establish a
pre-metastatic niche and promote CRLM. Cytokines such as CCL7
(91), IL-6 (92), IL-33 (93) and exosomes containing long
non-coding RNA MIR181A1HG (94)
also serve critical roles in inducing MDSC infiltration, enhancing
tumor invasiveness, supporting neovascularization and facilitating
the creation of a pre-metastatic ecological niche in the liver.
Targeted inhibition of these cytokines may offer an effective
therapeutic approach for CRLM.
DCs, as antigen-presenting cells, initiate immune
responses by capturing exogenous antigens and presenting them to T
cells. To evade immune surveillance, tumor cells suppress antigen
presentation by releasing inhibitory cytokines such as TGF-β
(95). Compared with DCs from
healthy individuals, those from patients with CRC exhibit impaired
antigen presentation, decreased expression of costimulatory
molecules, increased secretion of immunosuppressive IL-10 and
reduced levels of immunostimulatory IL-12 and TNF-α (96). Nagorsen et al (97) found that tumor-infiltrating
S100+ DCs in CRC are negatively associated with systemic
antigen-specific T cell responses and positively associated with
Tregs. Hsu et al (98)
discovered elevated CXCL1 expression in CRC patient-derived DCs,
which enhanced cell migration, increased matrix metalloproteinase 7
expression and promoted EMT, reflecting the altered functionality
of DCs within the CRC TME. Huang et al (99) revealed that tumor-associated
fibroblasts in CRC secrete WNT2, which suppresses DC function
through the JAK2/STAT3 pathway. Targeting WNT2 may restore
DC-mediated antitumor immunity. Further exploration of the
mechanisms regulating DC function in CRC may identify new
therapeutic targets for CRC treatment.
As a key component of innate immunity, NK cells
exert antitumor effects by releasing cytotoxic molecules such as
TRAIL and FasL. In a mouse model of CRLM, NK cells were shown to
inhibit liver metastasis of CRC (100). Increased NK cell infiltration is
associated with improved overall survival (OS) in patients with
CRLM (101).
However, NK cell function is impaired in both CRC
and liver metastases compared with NK cells in healthy livers. CRC
cells regulate the TME pH by producing lactic acid, which lowers
the pH within NK cells, leading to mitochondrial dysfunction and
apoptosis. This enables tumor cells to evade the cytotoxic effects
of NK cells (105). Metabolic
dysfunction in the metastatic niche notably impacts NK cell
functionality. Increased glutamine uptake by cancer cells depletes
glutamine availability for NK cells, decreasing their activity and
cytotoxicity, thereby promoting CRLM progression (106).
Upon entering the portal circulation, tumor cells
reach the hepatic sinusoidal capillaries through the portal vein.
These tumor cells trigger non-specific liver defense mechanisms,
leading to their phagocytosis by resident immune cells such as
Kupffer cells (KCs) and NK cells (107).
KCs, the resident macrophages of the liver, serve a
pivotal role in maintaining liver homeostasis and are key
contributors to the pathogenesis of liver disease. KCs are
essential in defending against liver metastasis due to their
phagocytic capability, cytokine production and promotion of
tertiary lymphoid structures (108). Dysfunction of phagocytosis in KCs
is a key driving force in CRLM. Some tumor cells can evade
phagocytosis by KCs, highlighting the need for further research
into this evasion mechanism to identify novel therapeutic targets
for liver metastasis (109). The
balance between pro-phagocytic ‘eat me’ signals, such as
tumor-associated antigens, calreticulin, SLAM Family Member 7 and
Erythroblast Membrane Associated Protein (ERMAP), and
anti-phagocytic ‘don't eat me’ signals, including CD47, PD-L1, CD24
and β2-microglobulin, is a key determinant in the phagocytosis
process (110). Additionally, the
functional reprogramming of KCs warrants attention. Following
metastatic colonization of the liver, KCs undergo transcriptional
reprogramming typical of TAMs, which facilitates tumor progression
(111). The phagocytosis of
exosomes released by the primary tumor into the circulation and
into the liver by KCs can initiate the formation of a
pre-metastatic niche in the liver (66).
Liver-resident specialized NK cells also serve a
significant role in the early stages of metastasis by contributing
to the establishment of pre-metastatic niches. Invariant NK T cells
in the liver promote metastasis by producing fibrogenic cytokines
such as IL-4 and IL-13, independent of T cell receptor activation,
thereby inducing a fibrotic niche in the liver. Targeted disruption
of IL-4 and IL-13 signaling pathways in hepatic stellate cells
inhibits their trans differentiation into extracellular
matrix-producing myofibroblasts, thereby impeding the metastatic
proliferation of disseminated cancer cells (112).
Tumor cells that evade innate immune surveillance
extravasate from blood vessels and form metastatic lesions. Tumor
cell adhesion to the vascular system is not only driven by
mechanical blockage of the vasculature, but also by specific
cellular adhesion processes that facilitate tumor cell attachment
and extravasation (113,114). Liver sinusoidal endothelial cells
express the cell adhesion molecule E-selectin, which promotes tumor
cell attachment to hepatic sinusoidal endothelial cells. Inhibition
of E-selectin effectively decreases the formation of liver
metastases (115). Moreover, tumor
cells can trigger the release of pro-inflammatory cytokines, such
as TNF-α, from KCs, which upregulates the expression of adhesion
molecules, such as E-selectin, vascular cell adhesion molecule 1
and intercellular adhesion molecule 1(ICAM1) on hepatic sinusoidal
endothelial cells. This increase in adhesion molecule expression
enhances tumor cell colonization in the liver (116).
Once tumor cells extravasate into the Disse
interstitium, hepatic stellate cells are activated by cytokines
such as TGF-β, which is secreted by KCs. This activation prompts
hepatic stellate cells to produce extracellular matrix proteins
such as collagen, laminin and fibronectin, creating a supportive
environment for tumor cell colonization. Additionally, KCs and
neutrophils secrete matrix metalloproteinases and elastases, which
degrade and remodel the extracellular matrix, facilitating tumor
cell invasion. Concurrently, hepatic stellate cells promote a
suppressive microenvironment by inducing the apoptosis of cytotoxic
T cells and expanding immune-regulatory T cells, creating a
favorable environment for tumor cell colonization in the liver
(117).
Research into liver metastasis in CRC has revealed
numerous potential therapeutic targets, with targeted therapy and
immunotherapy emerging as the leading strategies for managing CRLM
(121). In addition to traditional
neoadjuvant radiotherapy and chemotherapy and adjuvant therapy
following surgical resection, integrating targeted and
immunotherapies with radiotherapy/chemotherapy and surgery has
established a comprehensive treatment system for CRLM (122). This combination therapy offers
dual benefits: By initiating neoadjuvant treatment, previously
unresectable CRLM can become surgically resectable, increasing the
number of patients eligible for hepatic resection while decreasing
perioperative morbidity and mortality (123). Second, these combination therapies
show promise in enhancing long-term survival rates for patients
(124).
EGFR, a member of the receptor tyrosine kinase (TK)
family, serves a key role in CRC development and invasive
metastasis through downstream signaling pathways, including the
RAS/RAF/MEK/ERK and PI3K/AKT pathways (125). Cetuximab, the first monoclonal
antibody targeting EGFR, significantly improves OS and
progression-free survival (PFS) in patients with CRC who are
resistant to other treatment (126). When combined with chemotherapy,
cetuximab has demonstrated favorable therapeutic outcomes. The
combination of cetuximab with FOLFIRI (irinotecan, fluorouracil and
leucovorin) significantly decreases the risk of disease progression
in patients with mCRC compared with FOLFIRI alone (127). The combination of cetuximab with
FOLFOX4(oxaliplatin, leucovorin, and fluorouracil) as first-line
treatment for mCRC has also shown superior remission rates compared
with the FOLFOX4 regimen alone (128). However, mutations in the RAS gene
in CRC confer resistance to cetuximab, meaning cetuximab is
effective in patients with RAS wild-type mCRC (129) Another EGFR targeting drug,
panitumumab, is a fully humanized antibody that does not induce
antibody-dependent cell-mediated cytotoxicity (125). The PRIME trial, which examined the
efficacy of FOLFOX alone and in combination with panitumumab in
patients with mCRC, found that the combination therapy resulted in
higher OS and PFS compared with FOLFOX treatment alone (130,131).
Bevacizumab, a monoclonal antibody targeting the
angiogenesis inhibitor VEGF, has received US Food and Drug
Administration approval for the treatment of mCRC and demonstrated
favorable efficacy (132). A
meta-analysis by Cao et al (133), which included 1,838 patients with
mCRC, showed that chemotherapy combined with bevacizumab following
primary tumor resection significantly prolonged OS compared with
chemotherapy alone. The study also revealed improved OS in patients
who were initially unable to undergo resection of their primary
tumor when treated with bevacizumab. Additionally, the combination
of bevacizumab with chemotherapy may enhance the resectability of
CRLM. In a study by Tang et al (134), the combination of bevacizumab with
mFOLFOX6 as first-line treatment for patients with unresectable
CRLM harboring RAS mutations demonstrated significantly superior
efficacy compared with mFOLFOX6 monotherapy. This combination not
only markedly increased the R0 resection rate of liver metastases
but also improved the overall resectability of liver metastases,
leading to improved PFS and OS in patients. Ramucirumab, a VEGFR
antagonist that specifically binds VEGFR2 and blocks
ligand-receptor binding, has also shown promising results in mCRC
treatment (135). In a study by
Tabernero et al (136), the
combination of ramucirumab and FOLFIRI was evaluated against a
placebo in patients with mCRC. Ramucirumab and FOLFIRI combination
significantly improved OS in patients. Ramucirumab is currently
approved for use in the second-line treatment of mCRC.
Receptor TKs, located on the cell surface and
intracellularly, play a key role in intercellular signaling, which
influences cell function. TKIs block the activity of kinase
proteins that contribute to tumor cell proliferation and the
development of tumor vasculature. Regorafenib is an oral,
multi-targeted TKI that inhibits VEGFR1-3, PDGFR, FGFR, KIT, RET1
and BRAF and has been shown to improve survival in patients with
refractory mCRC (137).
Regorafenib is used to treat mCRC that progresses despite previous
chemotherapy, anti-VEGF or anti-EGFR therapy (138). In addition to regorafenib,
fruquintinib is an oral TKI that selectively inhibits different
subtypes of VEGFR, thereby inhibiting tumor angiogenesis and growth
(139). The FRESCO study evaluated
the effectiveness and safety of fruquintinib as a third-line or
subsequent treatment for patients with mCRC. The results
demonstrated that fruquintinib monotherapy significantly prolonged
survival in patients with mCRC who had failed second-line or higher
chemotherapy (140). FRESCO-2, an
international, multicentre, randomised, double-blind, phase 3
study, also demonstrated that fruquintinib significantly improved
overall survival in patients with refractory metastatic colorectal
cancer compared to placebo (141).
Fruquintinib is currently approved by FDA for use in patients with
mCRC who have previously undergone fluoropyrimidine-, oxaliplatin-,
and irinotecan-based chemotherapy, an anti-VEGF therapy, and if RAS
wild-type and medically appropriate, an anti-EGFR therapy (142).
In recent years, immune checkpoint inhibitors have
garnered attention due to their success in achieving long-lasting
responses in a range of previously difficult-to-treat solid tumors
(143). Overman et al
(144) demonstrated the
significant efficacy of the PD-1 inhibitor nivolumab alone in
individuals with deficient mismatch repair/microsatellite
instability(dMMR/MSI) CRC in a multicenter phase II clinical trial
(CheckMate142). Similarly, the KEYNOTE-177 (145) study showed a significant
improvement in PFS in patients with dMMR/MSI mCRC treated with the
PD-1 inhibitor pembrolizumab as first-line therapy, compared with
standard treatment. PD-1 inhibitors are currently approved by FDA
for patients with dMMR/MSI mCRC who experience disease progression
following standard chemotherapy (146). This approval highlights their
importance as a pivotal immunotherapy approach, particularly for
individuals with liver metastases from CRC. However, the efficacy
of PD-1 inhibitors varies among patients, and some do not benefit
from them. Patients with proficient mismatch repair/microsatellite
stability(pMMR/MSS) CRC, which constitutes the majority of the
patient population, derive limited benefits from PD-1 inhibitor
therapy. For individuals with dMMR/MSI CRC, who are currently
considered candidates for PD-1 inhibitor treatment, the observed
efficacy rate is suboptimal. In the KEYNOTE-016 trial,
pembrolizumab was administered to a cohort of 41 patients with CRC,
including both pMMR/MSS and dMMR/MSI subgroups, who experienced
disease progression following chemotherapy. In patients with
dMMR/MSI CRC, the immune-related objective response rate was 40%
and the 20-week PFS rate was 78%. By contrast, patients with
pMMR/MSS CRC exhibited an immune-related objective response rate of
0% and a 20-week PFS rate of 11% (147). Furthermore, liver metastases from
CRC induce systemic immune tolerance through a unique
immunosuppressive mechanism, which may further affect the efficacy
of PD-1 inhibitor therapy (148–150). Exploring effective combination
therapies may enhance the efficacy of PD-1 inhibitors. The
CheckMate-142 study demonstrated that combining PD-1 inhibitors
with CTLA4 inhibitors improves antitumor efficacy (151). In addition to immune checkpoint
inhibitors, drugs such as regorafenib have gained widespread
attention as potential combination therapies with PD-1 inhibitors
due to their promising role in modulating immunity and improving
the TME (152,153).
Cancer vaccines, adoptive cell transfer (ACT)
therapy and oncolytic viruses have emerged as prominent areas of
research in CRLM (154–156). As a form of active immunotherapy,
cancer vaccines present the immune system with tumor-specific or
-associated antigens, inducing antitumor cytotoxic responses that
help the immune system recognize and destroy cancer cells (157). ACT therapy enhances the natural
anti-cancer response by activating or genetically modifying
autologous or allogeneic immune cells in vitro to boost
tumor-fighting capabilities, followed by reinfusion into patients.
ACT includes therapies such as cytokine-induced killer cells and
chimeric antigen receptor T cell therapies (158). Oncolytic virus therapy uses
naturally occurring or genetically engineered viruses to
selectively target and lyse tumor cells. This strategy not only
modulates the TIME but also activates specific anti-tumor immune
responses (159). Additionally, it
is crucial to explore the role of cytokines, chemokines and
adjuvants in enhancing the precision and efficacy of
immunotherapies in CRLM.
Liver metastasis is a major factor influencing the
prognosis of patients with CRC. The process of liver metastasis in
CRC is complex and involves interconnected stages. Key pathways
that affect the invasive and metastatic potential of CRC cells have
been identified, along with prognostic and therapeutic molecules.
Additionally, factors within the TME influencing liver metastasis
in CRC have been preliminarily analyzed. Notably, the discovery of
immune-associated targets holds promise for treating liver
metastasis in CRC and improving prognosis. However, the clinical
application of these targets and associated drugs in individuals
with CRLM remains limited, and many patients do not benefit from
current targeted therapies and immunotherapies. Therapeutic
strategies aimed at modulating the immunosuppressive
microenvironment, such as depleting immunosuppressive cells,
inhibiting immune checkpoint pathways and stimulating cytotoxic
cells are critical approaches for enhancing the effectiveness of
immunotherapy.
Currently, novel immunotherapies for CRLM remain in
preclinical or clinical trials, and their successful integration
into clinical practice faces challenges. Firstly, CRLM creates a
highly immunosuppressive microenvironment within the liver. This
hostile TME actively inhibits the function of effector immune cells
(such as cytotoxic T cells and NK cells), rendering many
immunotherapies ineffective. Secondly, tumor heterogeneity and
evolution make it difficult to identify universal therapeutic
targets. Thirdly, lack of predictive biomarkers makes it difficult
to select patients most likely to benefit from expensive and
potentially toxic immunotherapies, leading to low response rates
and inefficient resource use. Lastly, overcoming the aforementioned
challenges above often requires combining immunotherapies (e.g.,
dual checkpoint blockade) with other modalities like chemotherapy,
targeted therapy (e.g., anti-VEGF, anti-EGFR), radiotherapy,
liver-directed therapies (ablation, embolization), or other
immunomodulators. Combinations significantly increase the risk of
severe immune-related adverse events (irAEs), including hepatitis,
colitis, pneumonitis, and endocrine toxicities. Managing
overlapping toxicities, especially in patients with liver
involvement, is challenging and can limit dosing or lead to
treatment discontinuation.
Overcoming these multifaceted challenges requires
further intensive studies to understand the CRLM biology and liver
immunology, elucidate the underlying mechanisms, discovering robust
biomarkers and identify novel therapeutic targets. Deeper
understanding of the key molecules and signaling pathways
influencing the invasive and metastatic potential of CRC is key,
achievable through the integration of high-throughput genomic
technology. Considering the complex and heterogeneous influence of
the TME on liver metastasis, it is necessary to investigate the
functional characteristics and dynamic changes of distinct cell
populations throughout the liver metastasis process, at a
single-cell level to identify key cells and molecules driving TME
remodeling. Moreover, as the understanding of the mechanisms
underlying CRLM advances, the diagnosis and treatment of this
condition may shift toward a multidisciplinary approach and enhance
patient care by facilitating a comprehensive and integrated
treatment strategy.
In conclusion, further research is required into the
mechanisms in CRLM, the exploration of novel targets for
personalized treatment and the development of innovative
intervention strategies to improve CRLM therapy efficacy.
Not applicable.
The present study was supported by the National Natural Science
Foundation of China (grant no. 82272841).
Not applicable.
CJY conceptualized the study and wrote the
manuscript. LZ performed the literature review. CHW and YJY
contributed to conception and design. ZLS revised and edited the
manuscript. Data authentication is not applicable. All authors have
read and approved the final manuscript.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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