Dan Liu
Yang Sun- Department of Biology, College of Basic Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
Metastatic liver cancer (MLC) remains a leading cause of cancer-related mortality due to the liver’s unique immunotolerant microenvironment and high vascularization. Key mechanisms involve KC-mediated fibronectin deposition, neutrophil extracellular traps (NETs), and MDSC-driven T-cell exhaustion. Clinically, therapeutic strategies targeting the tumor microenvironment (TME) such as CSF1R inhibition, CCR2/CCR5 blockade, and CD40 agonism show promise in preclinical and early-phase trials, especially when combined with immunotherapy. However, challenges remain in overcoming systemic immunosuppression. This review summarizes the dual roles of hepatic immune cells including Kupffer cells (KCs), neutrophils, and myeloid-derived suppressor cells (MDSCs) in either suppressing or promoting metastatic colonization. We elucidate how the liver’s immunological balance, governed by innate and adaptive responses, shifts toward immunosuppression during metastasis, fostering a pro-tumor niche. This synthesis of immunological insights underscores the potential of TME-modulating therapies to improve outcomes in MLC.
1 Introduction
Metastatic liver cancer (MLC) is a secondary malignancy arising from both gastrointestinal and non-gastrointestinal primary tumors. Gastrointestinal-derived metastases, though originating in the digestive tract, frequently disseminate to distant organs via hematogenous routes (1, 2). Due to the liver’s unique anatomical position and portal circulation, it serves as the predominant site for metastatic seeding in gastrointestinal cancers (3). MLC significantly contributes to cancer-related mortality (4, 5), with hepatic metastases conferring poor prognoses across malignancies, including breast, renal, and lung cancers. Notably, 25% of newly diagnosed CRC patients and 40%–50% with advanced CRC develop liver metastases (6).
The liver’s high metastatic susceptibility stems from its dual blood supply and hemodynamic architecture, which promote tumor cell homing (7). Beyond vascular mechanisms, the hepatic microenvironment critically supports metastatic colonization, making therapeutic targeting of the tumor microenvironment (TME) a key research focus (8, 9). This review summarizes the roles of hepatic immune cells, including Kupffer cells (KCs), neutrophils, and myeloid-derived suppressor cells (MDSCs), in either suppressing or promoting metastatic colonization. By synthesizing hepatic immune responses, microenvironmental dynamics, and clinical evidence, we explore TME modulation as a potential strategy for MLC prevention and therapy.
2 The unique hepatic immune microenvironment dictates the fate of metastatic cancer cells
2.1 Innate immune responses in the liver
The liver’s immune system is uniquely adapted to maintain tolerance to portal vein-derived antigens under homeostasis (10, 11), yet it can mount robust immune responses against acute threats like metastatic invasion (12). Upon entering the liver, cancer cells encounter a specialized cellular milieu that orchestrates antigen presentation, pathogen recognition, and targeted elimination (13). Natural killer (NK) cells dominate the hepatic lymphocyte population (14), playing a pivotal role in immune surveillance. Unlike adaptive immune cells, NK cells detect targets lacking MHC-I—a common evasion strategy employed by tumors and pathogens (15, 16). The liver also harbors invariant natural killer T (iNKT) cells, a unique subset derived from thymic CD4-CD8- precursors that mature into CD4+CD8+ effectors (17, 18). These cells express chemokine receptors (CCR5/CXCR3) and patrol liver sinusoids via CD1d-dependent interactions with liver sinusoidal endothelial cells (LSECs) and macrophages, enabling rapid anti-tumor responses (19, 20). However, during metastatic progression, iNKT cells exhibit functional impairment (21). Studies have shown that tumor-induced immunosuppressive cytokines, such as IL - 10 and TGF-β, downregulate their cytotoxic capacity and IFN-γ production. Additionally, the altered expression of CD1d and co-stimulatory molecules on antigen-presenting cells in the metastatic liver microenvironment diminishes iNKT cell activation (22, 23). This dysfunction facilitates immune evasion by metastatic cells and contributes to the establishment of an immunosuppressive niche. Beyond the resident Kupffer cells (KCs), the liver recruits CCR2+Ly6C+ monocytes from the bone marrow during inflammation (24). These monocytes are significantly upregulated in pathological states of the liver, and studies in CCR2-/- mice have demonstrated that their absence mitigates hepatic inflammation (25). Neutrophils are also actively recruited to sites of hepatic inflammation (26). These cells express adhesion molecules such as CD44, Siglec-9 (27), Siglec-10 (28), and very late antigen-4 (VLA - 4) (29), which mediate their adherence to vascular adhesion molecules on LSECs.
2.2 Adaptive immune responses in the liver
The liver maintains a delicate immunological equilibrium, balancing tolerance to dietary and microbial antigens with defense against pathogens and malignancies. This balance is orchestrated by hepatic antigen-presenting cells (APCs), which under steady-state conditions drive tolerogenic T cell responses, facilitating transplantation tolerance and chronic viral infections such as HBV and HCV (30, 31). LSECs function as tolerogenic APCs by expressing PD-L1 and inducing T cell exhaustion, suppressing Th1 differentiation while favoring IL - 4+ Th2 polarization. Meanwhile, KCs that resident liver macrophages exhibit low MHC II and co-stimulatory molecule (B7 - 1/2) expression, thereby limiting T cell activation and fostering immunosuppression via PD-L1 and cytokine secretion (32). However, upon stimulation with inflammatory cues such as TLR ligands, cytokines, and PolyI:C, KCs transition to an immunogenic phenotype, upregulating MHC II and activating iNKT cells, suggesting the existence of functionally distinct KC subsets (33, 34).
Hepatic dendritic cells (DCs), including CD11b+, CD11chigh, CD1c+, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs), generally suppress T cell activation. In mice, subsets like CD11c+CD8+ and CD11c+NK1.1+ DCs also exist but remain poorly characterized (32, 35). Hepatic mDCs and pDCs secrete IL - 10 and are regulated by macrophage colony-stimulating factor (M-CSF), which enhances IL - 10 while suppressing IL - 12 (36). pDCs also produce IL - 27 and IDO, promoting Treg expansion and immunosuppression (37, 38). Their low Delta4/Jagged1 Notch ligand ratio biases toward Th2 differentiation and CD4+ T cell apoptosis, reinforced by Treg-mediated inhibition and PD-L1–PD-1 signaling (39). Lipid-poor DCs tend to be tolerogenic; however, CD11c+CD8+ DCs elicit strong Th1 responses via IL - 12 and TNF-α, while CD11c+NK1.1+ DCs exhibit cytolytic activity and stimulate T cell immunity. Hepatocytes also present antigens via MHC II, contributing to antiviral defense, though their antitumor role remains uncertain (40). Hepatic stellate cells (HSCs), residing in the space of Disse, act as APCs and play a significant immunomodulatory role in the hepatic immune microenvironment. They express immune checkpoint molecules such as PD-L1 and secrete immunosuppressive mediators including IL - 6, IL - 10, and TGF-β, which collectively promote the expansion of regulatory T cells (Tregs) and contribute to the exhaustion of effector T cells (41–44). In addition, HSCs can express indoleamine 2,3-dioxygenase (IDO), further suppressing T cell proliferation and cytokine production through tryptophan depletion and kynurenine accumulation, thereby reinforcing immune tolerance (45, 46). Through CD44-dependent signaling, HSCs also convert recruited monocytes into myeloid-derived suppressor cells (MDSCs), exacerbating local immunosuppression and facilitating metastatic colonization (47). Overall, hepatic antigen presentation often favors immunosuppression, shaped by the dynamic interplay of tolerogenic and immunogenic signals within the hepatic microenvironment (Figure 1).
Figure 1. Immune microenvironment in metastatic liver cancer.
3 Pro-metastatic tumor microenvironment of the liver
3.1 Role of Kupffer cells in cancer cell metastasis
KCs, the liver’s resident macrophages, regulate cholesterol metabolism, pathogen clearance, and immune responses (48, 49). Originating from yolk sac-derived progenitors, KCs are replenished by bone marrow-derived precursors during hepatic injury or infection (50). They detect pathogens via diverse receptors, secreting cytokines to initiate innate immune responses (33, 51). KCs facilitate metastasis by forming a pre-metastatic niche. In pancreatic cancer, KCs internalize tumor-derived exosomes containing macrophage migration inhibitory factor, triggering TGF-β secretion and hepatic stellate cell (HSC)-mediated fibronectin production, promoting metastatic cell adhesion (52). Circulating tumor cells bind fibronectin via Talin-1, enhancing colonization (53). KCs exhibit dual roles in metastasis: early cytolysis versus later pro-tumor support. Depleting KCs increases metastatic burden, suggesting initial tumoricidal activity (54–56). KCs phagocytose tumor cells via Dectin-2 or other receptors, though post-internalization viability remains unclear (57). Cytotoxic NO, NK cell activation, and TNF-α secretion further limit early metastasis (58, 59). However, KC-derived cytokines may aid surviving tumor cells post-extravasation. Myeloid cell recruitment complicates KC-specific roles, as depletion strategies often affect other phagocytes. Thus, early-phase studies are critical to delineate KC contributions (57).
3.2 Role of neutrophils in cancer cell metastasis
One of the earliest pathological responses to hepatic cancer cell infiltration is neutrophil recruitment (60, 61). Normally, neutrophils migrate to inflamed sites by rolling along vascular endothelium via low-affinity binding to P-/E-selectins, followed by integrin-mediated firm adhesion and arrest, primarily in post-sinusoidal venules, though CD44-hyaluronan interactions are not involved in hepatic sinusoids (62). Tumor-associated neutrophils (TANs), like Kupffer cells, exhibit dual pro- and anti-metastatic roles (63). In colorectal liver metastases (CRLM), neutrophils promote progression, with elevated neutrophil-to-lymphocyte ratio (NLR) correlating with worse outcomes, though absolute neutrophil counts yield conflicting data (64). Higher neutrophil numbers generally predict poorer prognosis (65). Experimental models reveal neutrophils facilitate multiple metastatic steps (66). In pancreatic cancer GEMMs, they aid pre-metastatic niche formation, while neutrophil extracellular traps (NETs) enhance early cancer cell retention by physically ensnaring circulating tumor cells within the hepatic vasculature. Mechanistically, NETs release high-mobility group box 1 (HMGB1), which activates TLR9 signaling in tumor cells, promoting their proliferation and metastatic competency (67, 68). Moreover, NET-associated proteases such as neutrophil elastase and matrix metalloproteinase 9 (MMP9) degrade extracellular matrix (ECM) components, thereby facilitating tissue invasion and the establishment of a pro-metastatic niche (69, 70). Post-colonization, neutrophils accelerate growth via fibroblast growth factor 2 (FGF2), with FGF2 inhibition reducing metastatic burden (71). Neutrophils also modulate CD8+ T cell responses in metastatic liver cancer (MLC) and exhibit heterogeneous N1/N2 phenotypes regulated by TGF-β and IGF1, influencing pro- or anti-tumor effects (72, 73). Notably, transforming growth factor-β (TGF-β), secreted by metastatic tumor cells and Kupffer cells within the liver, is a key immunosuppressive cytokine that drives the polarization of neutrophils toward a pro-tumor phenotype (74, 75). TGF-β signaling inhibits neutrophil cytotoxicity and reactive oxygen species (ROS) production, while promoting the expression of matrix metalloproteinases MMP - 9 and vascular endothelial growth factor (VEGF) (76–79), thereby enhancing tumor angiogenesis and extracellular matrix remodeling. Moreover, TGF-β suppresses neutrophil-mediated stimulation of CD8+ T cell responses, further contributing to immune evasion in the metastatic tumor microenvironment (80, 81). In addition, IGF1 has been shown to further modulate the polarization of neutrophils, especially in liver metastasis, acting as a significant driver of the neutrophil polarization in this organ (82, 83). Thus, neutrophils drive metastasis at multiple stages, with TGF-β and IGF1 synergistically enhancing their pro-metastatic functions in liver metastases.
3.3 Recruitment of monocytes/macrophages and myeloid-derived suppressor cells to metastatic sites
Bone marrow-derived cells, including monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs), are recruited to the liver, facilitating metastatic expansion (84–86). In colorectal liver metastasis, macrophage infiltration is predominantly mediated by CCL9 and CCL15, which recruit CCR1+ macrophages, whereas granulocytic MDSCs are recruited via CCR2 (87, 88). Tumor-associated macrophages (TAMs) promote MLC growth, and their depletion reduces metastatic foci. Chemotactic factors drive macrophage recruitment, and blocking these signals attenuates metastasis. Kitamura et al. (89) identified CCL9 and CCL15 as CRC-secreted chemokines recruiting CCR1+ macrophages; CCR1 inhibition impairs infiltration and suppresses metastasis.
TAMs support metastasis via immune-dependent and independent mechanisms (90). They promote angiogenesis via VEGFR1, responding to tumor-derived VEGF and complement factors. CRC cells produce C5a, binding macrophage C5aR to enhance recruitment and M2 polarization, fostering metastasis. Conversely, C5aR ablation reduces M2 accumulation and metastatic burden (91, 92). In pancreatic cancer, macrophages secrete granulin, activating hepatic stellate cells (HSCs) to produce ECM and support metastasis. Lim et al. (93) found macrophage depletion upregulated S100A8/S100A9 and downregulated ANGPTL7 in cancer cells, altering metastatic potential. S100A8/A9 silencing reduced MLC formation, while ANGPTL7 overexpression suppressed it, indicating macrophage-mediated tumor reprogramming. Hypoxia in metastases enhances macrophage pro-metastatic functions (94). In HCC, hypoxia and necrosis induce HIF - 1α and TLR4 in macrophages, boosting IL - 1β production, ECM deposition, and metastasis (95). Cirrhotic mice show increased metastasis with reduced NO, while high-fat diet (HFD)-fed mice exhibit non-alcoholic fatty liver disease (NAFLD)-linked metastasis and M2 macrophage infiltration. NLRC4 deficiency abrogates HFD effects, and NAFLD-associated IL - 1β promotes HCC metastasis (96). Distinguishing resident from monocyte-derived macrophages is critical for therapy (97). Tumor secretomes homogenize macrophage populations toward pro-tumor phenotypes (98, 99), though ontogeny influences function, as CSF1R blockade affects brain microglia differently (100).
MDSCs suppress innate and adaptive immunity in metastasis (101, 102). M-MDSCs are often associated with immunosuppressive functions and T-cell inhibition, primarily through the production of arginase-1 and IDO, which impair T-cell function and promote Treg expansion (103). These M-MDSCs are frequently localized at the tumor stroma or the tumor periphery, where they interact with KCs and other stromal cells to suppress effector immune responses (104, 105). In contrast, G-MDSCs, which are typically characterized by the expression of Ly6G, mediate their immunosuppressive effects through neutrophil extracellular trap (NET) formation (106, 107). This mechanism facilitates the entrapment of circulating tumor cells in the hepatic vasculature and promotes tumor cell adhesion. Additionally, the release of HMGB1 by NETs activates TLR9 signaling in tumor cells, enhancing their metastatic potential (108). G-MDSCs are predominantly localized to microvascular niches within the hepatic sinusoids during early metastatic colonization, where they exert their pro-metastatic functions by altering the extracellular matrix (ECM) and promoting angiogenesis (109, 110). Recruited via LSEC/KC/HSC chemokines, their hepatic accumulation in female mice is estrogen-dependent and TNFR2-mediated (111). Tumor-derived VEGF induces macrophage CXCL1, recruiting MDSCs (112). STAT3 activation via sphingosine-1-phosphate receptor 1 (S1PR1) drives IL - 6-mediated MDSC accumulation (113), though signals preventing their maturation remain unclear (114). MDSCs are identified by CD11b, Ly6G, and Ly6C, but marker overlap with TAMs/TANs complicates characterization (115) (Table 1).
Table 1. Key immune cell populations in the hepatic metastatic niche and their functional roles.
3.4 Metabolic constraints of the tumor microenvironment impair immune effector functions
The immunosuppressive TME in metastatic liver cancer is not only shaped by cellular interactions but also by profound metabolic reprogramming that impairs cytotoxic immune responses (116, 117). Tumor cells consume glucose at a high rate through aerobic glycolysis (the Warburg effect), leading to glucose depletion in the hepatic niche (118, 119). Since both NK cells and cytotoxic CD8+ T cells rely on glucose-driven oxidative phosphorylation and aerobic glycolysis to sustain their effector functions, nutrient scarcity results in cellular exhaustion and reduced cytokine secretion (IFN-γ, TNF-α) (120, 121). Additionally, lactate—a byproduct of tumor glycolysis—is exported via MCT4 into the extracellular space (122, 123). Its accumulation acidifies the TME and is taken up by immune cells, causing intracellular acidosis that disrupts signaling pathways such as NFAT and mTOR, thereby suppressing IFN-γ production in NK and T cells (124). Moreover, hypoxia, a hallmark of the liver metastatic TME, stabilizes HIF - 1α in NK and T cells, shifting their metabolism toward anaerobic pathways and impairing mitochondrial function, proliferation, and cytolytic activity (120, 125). Collectively, these metabolic stressors within the TME undermine the survival and effector potency of immune cells, further favoring metastatic colonization.
4 Clinical trials targeting TAMs and MDSCs
TAMs and MDSCs critically sustain the immunotolerant milieu of metastatic liver cancer (MLC), making them prime therapeutic targets (126, 127). The CSF1/CSF1R axis regulates macrophage differentiation, recruitment, and survival. CSF1R inhibitors reduce CD68+/CD163+ macrophage infiltration in normal liver tissue. In colorectal cancer (CRC) models, CSF1R blockade elevates cytotoxic T cells while suppressing FoxP3+ Tregs (128). Though limited as monotherapy (129), CSF1R inhibition synergizes with PD - 1/PD-L1 inhibitors or chemotherapy. A phase I trial (NCT02777710) combining durvalumab (PD-L1 inhibitor) and pexidartinib (CSF1R inhibitor) in advanced CRC/pancreatic cancer showed 21% achieving stable disease ≥2 months (130). This limited efficacy of CSF1R blockade as monotherapy may stem from compensatory mechanisms that sustain TAM survival and function (131, 132). In particular, GM-CSF and G-CSF signaling pathways can support macrophage viability and polarization in the absence of CSF1R signaling, enabling the persistence of pro-tumoral macrophage populations despite CSF1R inhibition (133, 134). Additionally, tumors may circumvent CSF1R blockade by recruiting alternative immunosuppressive cell types, including tumor-associated neutrophils (TANs), MDSCs, and tolerogenic dendritic cells, which collectively reinforce an immunosuppressive microenvironment (135). These compensatory pathways highlight the need for combination therapies that simultaneously target multiple immunoregulatory axes within the tumor microenvironment.
Disrupting TAM/MDSC recruitment offers another strategy. CCL2, CXCL12, and CCL5 mediate hepatic infiltration by these cells (136, 137). In CRC models, CCL2 correlates with MLC progression. CCR2 knockout mice exhibit reduced TAMs, increased CD8+/CD4+ T cells, and improved survival (138). Clinically, the CCR2 antagonist CCX872 plus FOLFIRINOX improved survival in metastatic pancreatic cancer, with ~33% alive at 18 months (139). An ongoing trial (NCT03184870) is testing the CCR2/CCR5 antagonist BMS - 813160 with chemo/immunotherapy in metastatic pancreatic/CRC. The CXCL12/CXCR4 axis also recruits immunosuppressive cells to the liver (140). In CRC models, CXCR4 inhibition reduced MLC/MDSC accumulation (141) and enhanced PD - 1 blockade efficacy, elevating CD8+ T cell/Treg ratios and tumor regression (142). A trial combining the CXCR4 inhibitor BL - 8040 with FOLFIRI/pembrolizumab in refractory pancreatic cancer yielded 4 partial responses among 15 patients (143). Further trials (NCT02907099) will clarify its role in MLC.
The CCL5/CCR5 axis drives metastasis by mobilizing MDSCs and polarizing M2 macrophages (144, 145). In CRLM, CCR5+ tumors exhibit elevated Treg: CTL ratios and PD - 1/CTLA-4 (146). Preclinical data show CCL5 boosts TAM-derived MMPs, accelerating progression, while maraviroc (CCR5 inhibitor) reprograms TAMs to an antitumoral phenotype. A phase I trial (MARACON) in CCR5+ mCRC saw 3/11 patients respond post-chemotherapy (147). Ongoing studies (NCT03274804, NCT03631407) are testing CCR5/PD-1 co-blockade in MSS mCRC. Reprogramming TAMs toward antitumor states is another approach. CD47-SIRPα signaling inhibits macrophage phagocytosis, and CD47 upregulation helps tumors evade immunity (148). In models, CD47 inhibition reduced MLC (149), prompting phase I trials of CD47 blockers alone (NCT04257617, NCT03763149) or combined (NCT02953782). CD40 agonists activate macrophages via T cell-dependent/independent pathways, inducing IFN production and ECM remodeling (150). A phase Ib trial combining gemcitabine/nab-paclitaxel/CD40 agonist ± nivolumab in metastatic pancreatic cancer achieved a 58% response rate (151). Other agents promoting M1 polarization include TLR agonists, PI3Kγ inhibitors, and HDAC inhibitors (152–154). The liver’s immunotolerant microenvironment is shaped by bone marrow/lymphoid-derived immunosuppressive cells, fostering metastasis and impairing systemic immunity. Overcoming this requires multimodal strategies, with current research focusing on enhancing immunotherapy efficacy in MLC.
5 Conclusion
Metastatic liver cancer (MLC) represents a formidable clinical challenge, where the liver’s unique immunotolerant microenvironment actively facilitates tumor colonization and progression. Our review highlights the dual roles of hepatic immune cells - initially serving as a defense barrier but ultimately being co-opted to support metastatic growth through multiple mechanisms. Kupffer cells transition from tumoricidal effectors to pro-metastatic facilitators, while recruited neutrophils and MDSCs establish immunosuppressive networks via NETosis, cytokine secretion, and metabolic competition. These cellular interactions create a self-reinforcing niche that promotes immune evasion and treatment resistance.
To overcome these challenges, future therapeutic strategies must integrate TME-modulating agents with immunotherapy and chemotherapy, guided by comprehensive immune profiling. Emphasis should be placed on identifying predictive biomarkers and understanding spatiotemporal immune evolution during metastasis. By elucidating the complex immunobiology of liver metastasis, this review highlights the potential of combinatorial approaches to transform MLC treatment and improve patient outcomes.
Author contributions
DL: Writing – original draft. ML: Writing – original draft. YL: Writing – original draft. FX: Writing – original draft. RL: Writing – original draft. YS: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research and/or publication of this article. This work was supported by National Natural Science Foundation of China (81704054).
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.
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References
1. Itoh A, Shibuya K, Kimura N, Fukasawa M, Kawai S, Igarashi T, et al. Successful conversion surgery for patients with pancreatic cancer, positive peritoneal cytology, and liver metastasis who were treated with chemotherapy involving nanoliposomal irinotecan with fluorouracil and folinic acid. Clin J Gastroenterol. (2025). doi: 10.1007/s12328-025-02175-2
2. Noguchi Y, Einama T, Ohara M, Ichio K, Kobayashi K, Yonamine N, et al. Gadoxetic acid-enhanced magnetic resonance imaging to predict pathologic complete response of colorectal liver metastases in preoperative chemotherapy. Sci Rep. (2025) 15:22632. doi: 10.1038/s41598-025-08243-4
3. Dong D, Yu X, Xu J, Yu N, Liu Z, and Sun Y. Cellular and molecular mechanisms of gastrointestinal cancer liver metastases and drug resistance. Drug Resist Update. (2024) 77:101125. doi: 10.1016/j.drup.2024.101125
4. Purl MC, Shick A, Canter RJ, and Judge SJ. Tracking cellular therapies to optimize homing against liver metastases. Front Immunol. (2025) 16:1611861. doi: 10.3389/fimmu.2025.1611861
5. Qin Y, Wang C, Xu S, Zhou J, Li S, and Ye H. S100a4 promotes metastatic transformation in non-metastatic liver cancer cells through NMIIa binding: mechanistic insights. BMC Cancer. (2025) 25:1144. doi: 10.1186/s12885-025-14502-4
6. Tsilimigras DI, Brodt P, Clavien PA, Muschel RJ, D’Angelica MI, Endo I, et al. Liver metastases. Nat Rev Dis Primers. (2021) 7:27. doi: 10.1038/s41572-021-00261-6
7. Wu YD, Huang XX, Zhang HX, Pan Y, Xie CK, Li G, et al. TRAF3IP2-AS1 deficiency induces necroptosis to promote pancreatic cancer liver metastasis. Cancer Res. (2025). doi: 10.1158/0008-5472.CAN-24-4784
8. Yu C, Lu W, Wu J, Fang X, Wang X, Zhang G, et al. Liver metastasis or peritoneal metastasis: single-cell RNA sequencing reveals the organotropism in colorectal cancer is driven by distinct partial-EMT processes. Cancer Lett. (2025) 629:217880. doi: 10.1016/j.canlet.2025.217880
9. Xie H, Xi X, Lei T, Liu H, and Xia Z. CD8(+) T cell exhaustion in the tumor microenvironment of breast cancer. Front Immunol. (2024) 15:1507283. doi: 10.3389/fimmu.2024.1507283
10. Lei H, Reinke P, Volk HD, Lv Y, and Wu R. Mechanisms of immune tolerance in liver transplantation-crosstalk between alloreactive T cells and liver cells with therapeutic prospects. Front Immunol. (2019) 10:2667. doi: 10.3389/fimmu.2019.02667
11. Zhai X, Xia Z, Du G, Zhang X, Xia T, Ma D, et al. LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance. Genes Dis. (2023) 10:2082–96. doi: 10.1016/j.gendis.2022.10.021
12. Ciner AT, Jones K, Muschel RJ, and Brodt P. The unique immune microenvironment of liver metastases: Challenges and opportunities. Semin Cancer Biol. (2021) 71:143–56. doi: 10.1016/j.semcancer.2020.06.003
13. Llovet JM, Castet F, Heikenwalder M, Maini MK, Mazzaferro V, Pinato DJ, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. (2022) 19:151–72. doi: 10.1038/s41571-021-00573-2
14. Shin SK, Oh S, Chun SK, Ahn MJ, Lee SM, Kim K, et al. Immune signature and therapeutic approach of natural killer cell in chronic liver disease and hepatocellular carcinoma. J Gastroenterol Hepatol. (2024) 39:1717–27. doi: 10.1111/jgh.16584
15. Zhang H, Yuan Z, Wang J, Tang Q, Miao Y, Yuan Z, et al. Triptolide leads to hepatic intolerance to exogenous lipopolysaccharide and natural-killer-cell mediated hepatocellular damage by inhibiting MHC class I molecules. Phytomedicine. (2023) 109:154621. doi: 10.1016/j.phymed.2022.154621
16. Russo E, D’Aquino C, Di Censo C, Laffranchi M, Tomaipitinca L, Licursi V, et al. Cxcr3 promotes protection from colorectal cancer liver metastasis by driving NK cell infiltration and plasticity. J Clin Invest. (2025) 135:e184036. doi: 10.1172/JCI184036
17. Cheng X, Tan X, Wang W, Zhang Z, Zhu R, Wu M, et al. Long-chain acylcarnitines induce senescence of invariant natural killer T cells in hepatocellular carcinoma. Cancer Res. (2023) 83:582–94. doi: 10.1158/0008-5472.CAN-22-2273
18. Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S, Harada M, et al. Alternative pathway for the development of V(α)14(+) NKT cells directly from CD4(-)CD8(-) thymocytes that bypasses the CD4(+)CD8(+) stage. Nat Immunol. (2017) 18:274–82. doi: 10.1038/ni.3668
19. Slauenwhite D and Johnston B. Regulation of NKT cell localization in homeostasis and infection. Front Immunol. (2015) 6:255. doi: 10.3389/fimmu.2015.00255
20. Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, et al. Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids. PLoS Biol. (2005) 3:e113. doi: 10.1371/journal.pbio.0030113
21. Yi Q, Wang J, Liu T, Yao Y, Loveless I, Subedi K, et al. scRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic cancer liver metastasis. Cancer Lett. (2023) 561:216149. doi: 10.1016/j.canlet.2023.216149
22. Iwabuchi K, Satoh M, Yoshino K, and Ishimori N. Recent advances regarding the potential roles of invariant natural killer T cells in cardiovascular diseases with immunological and inflammatory backgrounds. Int Immunol. (2024) 36:377–92. doi: 10.1093/intimm/dxae019
23. Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Yamamoto M, Fujita Y, et al. Decreased expressions of CD1d molecule on liver dendritic cells in subcutaneous tumor bearing mice. J Hepatol. (2008) 49:779–86. doi: 10.1016/j.jhep.2008.06.011
24. Shi C, Velázquez P, Hohl TM, Leiner I, Dustin ML, and Pamer EG. Monocyte trafficking to hepatic sites of bacterial infection is chemokine independent and directed by focal intercellular adhesion molecule-1 expression. J Immunol. (2010) 184:6266–74. doi: 10.4049/jimmunol.0904160
25. Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology. (2016) 64:1667–82. doi: 10.1002/hep.28682
26. Yang Y, Yu S, Lv C, and Tian Y. NETosis in tumour microenvironment of liver: From primary to metastatic hepatic carcinoma. Ageing Res Rev. (2024) 97:102297. doi: 10.1016/j.arr.2024.102297
27. Wu Y, Huang W, Xie Y, Wang C, Luo N, Chen Y, et al. Siglec-9, a putative immune checkpoint marker for cancer progression across multiple cancer types. Front Mol Biosci. (2022) 9:743515. doi: 10.3389/fmolb.2022.743515
28. Wang C, He L, Peng J, Lu C, Zhang M, Qi X, et al. Identification of Siglec-10 as a new dendritic cell checkpoint for cervical cancer immunotherapy. J Immunother Cancer. (2024) 12:e009404. doi: 10.1136/jitc-2024-009404
29. Reyes-González JM, Rajkumar H, Lee W, Baidoo KE, Edinger RS, Diehl G, et al. Evaluation of VLA - 4 (Integrin α4β1) as a shared target for radiopharmaceutical therapy across solid tumors. Mol Cancer Ther. (2025) 24:896–906. doi: 10.1158/1535-7163.MCT-24-0370
30. Kato R. Reactive metabolites cause idiosyncratic drug-induced liver injury via inflammasome activation in antigen-presenting cells. J Appl Toxicol. (2025) 45:1223–9. doi: 10.1002/jat.4751
31. Bettens F, Tiercy JM, Campanile N, Giostra E, Majno P, Rubbia L, et al. Microchimerism after liver transplantation: absence of rejection without abrogation of anti-donor cytotoxic T-lymphocyte-mediated alloreactivity. Liver Transpl. (2005) 11:290–7. doi: 10.1002/lt.20360
32. Doherty DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review. J Autoimmun. (2016) 66:60–75. doi: 10.1016/j.jaut.2015.08.020
33. Narmada BC, Khakpoor A, Shirgaonkar N, Narayanan S, Aw PPK, Singh M, et al. Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity. J Hepatol. (2024) 81:42–61. doi: 10.1016/j.jhep.2024.02.017
34. David BA, Rezende RM, Antunes MM, Santos MM, Freitas Lopes MA, Diniz AB, et al. Combination of mass cytometry and imaging analysis reveals origin, location, and functional repopulation of liver myeloid cells in mice. Gastroenterology. (2016) 151:1176–91. doi: 10.1053/j.gastro.2016.08.024
35. Méndez-Sánchez N, Córdova-Gallardo J, Barranco-Fragoso B, and Eslam M. Hepatic dendritic cells in the development and progression of metabolic steatohepatitis. Front Immunol. (2021) 12:641240. doi: 10.3389/fimmu.2021.641240
36. Bamboat ZM, Stableford JA, Plitas G, Burt BM, Nguyen HM, Welles AP, et al. Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol. (2009) 182:1901–11. doi: 10.4049/jimmunol.0803404
37. Zhong Q, Lu Y, Xu W, Rong Z, Chang X, Qin L, et al. The differentiation of new human CD303(+) Plasmacytoid dendritic cell subpopulations expressing CD205 and/or CD103 regulated by Non-Small-Cell lung cancer cells. Int Immunopharmacol. (2021) 99:107983. doi: 10.1016/j.intimp.2021.107983
38. Yang L, Ma J, He Q, and Li X. Immutol regulates CD4(+)Tregs, CD8(+)Tregs and pDCs via IDO signaling pathway to induce immune tolerance in rat heart allograft transplant. Transpl Immunol. (2021) 68:101393. doi: 10.1016/j.trim.2021.101393
39. Kun W, Xiaomei C, Lei Y, and Huizhi Z. Modulating Th1/Th2 drift in asthma-related immune inflammation by enhancing bone mesenchymal stem cell homing through targeted inhibition of the Notch1/Jagged1 signaling pathway. Int Immunopharmacol. (2024) 130:111713. doi: 10.1016/j.intimp.2024.111713
40. Kubes P and Jenne C. Immune responses in the liver. Annu Rev Immunol. (2018) 36:247–77. doi: 10.1146/annurev-immunol-051116-052415
41. Zhang Y, Li X, Chen H, Li J, Guo X, Fang Y, et al. Cancer cell-derived exosomal miR-500a-3p modulates hepatic stellate cell activation and the immunosuppressive microenvironment. Adv Sci (Weinh). (2025) 12:e2404089. doi: 10.1002/advs.202404089
42. Kasahara N, Imi Y, Amano R, Shinohara M, Okada K, Hosokawa Y, et al. A gut microbial metabolite of linoleic acid ameliorates liver fibrosis by inhibiting TGF-β signaling in hepatic stellate cells. Sci Rep. (2023) 13:18983. doi: 10.1038/s41598-023-46404-5
43. Zhu Y, Gu J, Lu Y, Tao Q, Cao X, Zhu Y, et al. IL - 6 released from hepatic stellate cells promotes glycolysis and migration of HCC through the JAK1/vWF/TGFB1 axis. J Hepatocell Carcinoma. (2024) 11:1295–310. doi: 10.2147/JHC.S464880
44. Li Z, Zhang C, Huang G, Zhang Z, Wang Q, Liu X, et al. Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1/FASN/ACC pathway and anti-inflammatory effect of IL10. Cell Death Dis. (2025) 16:245. doi: 10.1038/s41419-025-07500-8
45. Cheng JT, Deng YN, Yi HM, Wang GY, Fu BS, Chen WJ, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL - 6-mediated STAT3 activation. Oncogenesis. (2016) 5:e198. doi: 10.1038/oncsis.2016.7
46. Charehjoo A, Majidpoor J, and Mortezaee K. Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated. Int Immunopharmacol. (2023) 118:110032. doi: 10.1016/j.intimp.2023.110032
47. Hagenstein J, Burkhardt S, Sprezyna P, Tasika E, Tiegs G, and Diehl L. CD44 expression on murine hepatic stellate cells promotes the induction of monocytic and polymorphonuclear myeloid-derived suppressor cells. J Leukoc Biol. (2024) 116:177–85. doi: 10.1093/jleuko/qiae053
48. Modares NF, Hendrikse LD, Smith LK, Paul MS, Haight J, Luo P, et al. B cell-derived acetylcholine promotes liver regeneration by regulating Kupffer cell and hepatic CD8(+) T cell function. Immunity. (2025) 58:1201–1216.e1207. doi: 10.1016/j.immuni.2025.04.002
49. Hong H, Tu T, Alhousari D, He L, Aggarwal R, Debebe A, et al. Characterizing kupffer cell production of CD5L and its function on regulating migration of natural killer T cells. Am J Pathol. (2025). doi: 10.1016/j.ajpath.2025.06.003
50. Wen Y, Lambrecht J, Ju C, and Tacke F. Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities. Cell Mol Immunol. (2021) 18:45–56. doi: 10.1038/s41423-020-00558-8
51. Lu WP, Liu YD, Zhang ZF, Liu J, Ye JW, Wang SY, et al. m(6)A-modified MIR670HG suppresses tumor liver metastasis through enhancing Kupffer cell phagocytosis. Cell Mol Life Sci. (2025) 82:185. doi: 10.1007/s00018-025-05700-1
52. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. (2015) 17:816–26. doi: 10.1038/ncb3169
53. Barbazán J, Alonso-Alconada L, Elkhatib N, Geraldo S, Gurchenkov V, Glentis A, et al. Liver metastasis is facilitated by the adherence of circulating tumor cells to vascular fibronectin deposits. Cancer Res. (2017) 77:3431–41. doi: 10.1158/0008-5472.CAN-16-1917
54. Cao J, Qin S, Li B, Zhang Z, Miao P, Yan H, et al. Extracellular vesicle-induced lipid dysregulation drives liver premetastatic niche formation in colorectal cancer. Gut. (2025). doi: 10.1136/gutjnl-2025-334851
55. Liu Y, Zhai Y, Zhang Y, Song L, Zhang H, Cao J, et al. High metastatic tumor-derived CXCL16 mediates liver colonization metastasis by inducing Kupffer cell polarization via the PI3K/AKT/FOXO3a pathway. Neoplasia. (2025) 65:101174. doi: 10.1016/j.neo.2025.101174
56. Wen SW, Ager EI, and Christophi C. Bimodal role of Kupffer cells during colorectal cancer liver metastasis. Cancer Biol Ther. (2013) 14:606–13. doi: 10.4161/cbt.24593
57. Kimura Y, Inoue A, Hangai S, Saijo S, Negishi H, Nishio J, et al. The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis. Proc Natl Acad Sci U S A. (2016) 113:14097–102. doi: 10.1073/pnas.1617903113
58. Wiltrout RH. Regulation and antimetastatic functions of liver-associated natural killer cells. Immunol Rev. (2000) 174:63–76. doi: 10.1034/j.1600-0528.2002.00014h.x
59. Wang G, Li J, Bojmar L, Chen H, Li Z, Tobias GC, et al. Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature. (2023) 618:374–82. doi: 10.1038/s41586-023-06114-4
60. Jiang Y, Long G, Huang X, Wang W, Cheng B, and Pan W. Single-cell transcriptomic analysis reveals dynamic changes in the liver microenvironment during colorectal cancer metastatic progression. J Transl Med. (2025) 23:336. doi: 10.1186/s12967-025-06351-3
61. Li P, Fan F, Zhang B, Yuan C, and Liang H. Neutrophil spatiotemporal regulatory networks: dual roles in tumor growth regulation and metastasis. Biomedicines. (2025) 13:1473. doi: 10.3390/biomedicines13061473
62. McDonald B, McAvoy EF, Lam F, Gill V, de la Motte C, Savani RC, et al. Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids. J Exp Med. (2008) 205:915–27. doi: 10.1084/jem.20071765
63. Gao X, Xu M, Xiao H, Han Z, Wang Z, Sun G, et al. Tumor-associated neutrophils: A complex role in cancer. Clin Immunol. (2025) 280:110558. doi: 10.1016/j.clim.2025.110558
64. He W, Yin C, Guo G, Jiang C, Wang F, Qiu H, et al. Initial neutrophil lymphocyte ratio is superior to platelet lymphocyte ratio as an adverse prognostic and predictive factor in metastatic colorectal cancer. Med Oncol. (2013) 30:439. doi: 10.1007/s12032-012-0439-x
65. Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, et al. Epithelial NOTCH signaling rewires the tumor microenvironment of colorectal cancer to drive poor-prognosis subtypes and metastasis. Cancer Cell. (2019) 36:319–336.e317. doi: 10.1016/j.ccell.2019.08.003
66. Zhou M, Guan B, Liu Y, Gu Q, Chen W, Xie B, et al. Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation. Cancer Lett. (2025) 618:217642. doi: 10.1016/j.canlet.2025.217642
67. Sun W, Xu J, Li S, Zhao Y, Fu J, Di L, et al. GLUT1-mediated HMGB1 O-GlcNAcylation drives hyperglycemia-Induced neutrophil extracellular trap networks formation via TLR4 signaling and exacerbates fibroblast inflammation. Sci Rep. (2025) 15:18853. doi: 10.1038/s41598-025-03642-z
68. Miao N, Kang Z, Wang Z, Yu W, Liu T, Kong LZ, et al. Mitochondrial reactive oxygen species promote cancer metastasis and tumor microenvironment immunosuppression through gasdermin D. Cell Death Discov. (2025) 11:219. doi: 10.1038/s41420-025-02516-7
69. He Y, Hou S, and Memg C. Neutrophil extracellular traps activates focal adhesion kinase by upregulating MMP9 expression to promote proliferation and migration of mouse colorectal cancer cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. (2023) 39:416–22.
70. Wu L, Saxena S, Goel P, Prajapati DR, Wang C, and Singh RK. Breast cancer cell-neutrophil interactions enhance neutrophil survival and pro-tumorigenic activities. Cancers (Basel). (2020) 12:2884. doi: 10.3390/cancers12102884
71. Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Markelc B, Kim KJ, et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology. (2017) 65:1920–35. doi: 10.1002/hep.29088
72. Wu X, Chen J, Chen Y, Song S, Fang Y, Mao S, et al. Targeting deltex E3 ubiquitin ligase 2 inhibits tumor-associated neutrophils and sensitizes hepatocellular carcinoma cells to immunotherapy. Adv Sci (Weinh). (2025) 12:e2408233. doi: 10.1002/advs.202408233
73. Giese MA, Hind LE, and Huttenlocher A. Neutrophil plasticity in the tumor microenvironment. Blood. (2019) 133:2159–67. doi: 10.1182/blood-2018-11-844548
74. Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q, et al. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct Target Ther. (2024) 9:236. doi: 10.1038/s41392-024-01937-7
75. Tauriello DVF, Palomo-Ponce S, Stork D, Berenguer-Llergo A, Badia-Ramentol J, Iglesias M, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. (2018) 554:538–43. doi: 10.1038/nature25492
76. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell. (2009) 16:183–94. doi: 10.1016/j.ccr.2009.06.017
77. Zhang F, Yan Y, Cao X, Guo C, Wang K, and Lv S. TGF-β-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer. Cell Death Dis. (2024) 15:218. doi: 10.1038/s41419-024-06594-w
78. Hein LE, SenGupta S, Gunasekaran G, Johnson CN, and Parent CA. TGF-β1 activates neutrophil signaling and gene expression but not migration. PLoS One. (2023) 18:e0290886. doi: 10.1371/journal.pone.0290886
79. Kochumon S, Al-Sayyar A, Jacob T, Bahman F, Akhter N, Wilson A, et al. TGF-β and TNF-α interaction promotes the expression of MMP - 9 through H3K36 dimethylation: implications in breast cancer metastasis. Front Immunol. (2024) 15:1430187. doi: 10.3389/fimmu.2024.1430187
80. Lemaitre L, Adeniji N, Suresh A, Reguram R, Zhang J, Park J, et al. Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease. Nat Cancer. (2024) 5:1534–56. doi: 10.1038/s43018-024-00828-8
81. Lan Y, Moustafa M, Knoll M, Xu C, Furkel J, Lazorchak A, et al. Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion. Cancer Cell. (2021) 39:1388–1403.e1310. doi: 10.1016/j.ccell.2021.08.008
82. Mizuno R, Kawada K, Itatani Y, Ogawa R, Kiyasu Y, and Sakai Y. The role of tumor-associated neutrophils in colorectal cancer. Int J Mol Sci. (2019) 20:529. doi: 10.3390/ijms20030529
83. Rayes RF, Milette S, Fernandez MC, Ham B, Wang N, Bourdeau F, et al. Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency. Oncotarget. (2018) 9:15691–704. doi: 10.18632/oncotarget.24593
84. Conche C, Finkelmeier F, Pešić M, Nicolas AM, Böttger TW, Kennel KB, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. (2023) 72:1774–82. doi: 10.1136/gutjnl-2022-327909
85. Tang X, Gao L, Jiang X, Hou Z, Wang Y, Hou S, et al. Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis. Oncogene. (2024) 43:2635–46. doi: 10.1038/s41388-024-03114-0
86. Deng Y, Shi M, Yi L, Naveed Khan M, Xia Z, and Li X. Eliminating a barrier: Aiming at VISTA, reversing MDSC-mediated T cell suppression in the tumor microenvironment. Heliyon. (2024) 10:e37060. doi: 10.1016/j.heliyon.2024.e37060
87. Liu Y, Zhang Q, Xing B, Luo N, Gao R, Yu K, et al. Immune phenotypic linkage between colorectal cancer and liver metastasis. Cancer Cell. (2022) 40:424–437.e425. doi: 10.1016/j.ccell.2022.02.013
88. Sun X, Zhang J, Dong B, Xiong Q, Wang X, Gu Y, et al. Targeting SLITRK4 restrains proliferation and liver metastasis in colorectal cancer via regulating PI3K/AKT/NFκB pathway and tumor-associated macrophage. Adv Sci (Weinh). (2025) 12:e2400367. doi: 10.1002/advs.202400367
89. Kitamura T, Fujishita T, Loetscher P, Revesz L, Hashida H, Kizaka-Kondoh S, et al. Inactivation of chemokine (C-C motif) receptor 1 (CCR1) suppresses colon cancer liver metastasis by blocking accumulation of immature myeloid cells in a mouse model. Proc Natl Acad Sci U S A. (2010) 107:13063–8. doi: 10.1073/pnas.1002372107
90. Gao Y, Yuan W, Zhang J, Wang Z, Cui W, and Guan Z. A two-decade bibliometric analysis of tumor-associated macrophages in colorectal cancer research. Hum Vaccin Immunother. (2025) 21:2512656. doi: 10.1080/21645515.2025.2512656
91. Piao C, Zhang WM, Li TT, Zhang CC, Qiu S, Liu Y, et al. Complement 5a stimulates macrophage polarization and contributes to tumor metastases of colon cancer. Exp Cell Res. (2018) 366:127–38. doi: 10.1016/j.yexcr.2018.03.009
92. Zhai X, Zhang H, Xia Z, Liu M, Du G, Jiang Z, et al. Oxytocin alleviates liver fibrosis via hepatic macrophages. JHEP Rep. (2024) 6:101032. doi: 10.1016/j.jhepr.2024.101032
93. Lim SY, Gordon-Weeks A, Allen D, Kersemans V, Beech J, Smart S, et al. Cd11b(+) myeloid cells support hepatic metastasis through down-regulation of angiopoietin-like 7 in cancer cells. Hepatology. (2015) 62:521–33. doi: 10.1002/hep.27838
94. Meng C, Lin K, Shi W, Teng H, Wan X, DeBruine A, et al. Histone methyltransferase ASH1L primes metastases and metabolic reprogramming of macrophages in the bone niche. Nat Commun. (2025) 16:4681. doi: 10.1038/s41467-025-59381-2
95. Zhang J, Zhang Q, Lou Y, Fu Q, Chen Q, Wei T, et al. Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. (2018) 67:1872–89. doi: 10.1002/hep.29681
96. Ohashi K, Wang Z, Yang YM, Billet S, Tu W, Pimienta M, et al. NOD-like receptor C4 inflammasome regulates the growth of colon cancer liver metastasis in NAFLD. Hepatology. (2019) 70:1582–99. doi: 10.1002/hep.30693
97. Bi Q, Wang M, Luo L, Zhang B, Lv S, Wang Z, et al. Wenxia Changfu Formula inhibits NSCLC metastasis by halting TAMs-induced epithelial-mesenchymal transition via antagonisticallymodulating CCL18. Chin J Nat Med. (2025) 23:838–47. doi: 10.1016/S1875-5364(25)60912-5
98. van de Laar L, Saelens W, De Prijck S, Martens L, Scott CL, Van Isterdael G, et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity. (2016) 44:755–68. doi: 10.1016/j.immuni.2016.02.017
99. Garavaglia B, Vallino L, Ferraresi A, Amoruso A, Pane M, and Isidoro C. Probiotic-derived metabolites from lactiplantibacillus plantarum OC01 reprogram tumor-associated macrophages to an inflammatory anti-tumoral phenotype: impact on colorectal cancer cell proliferation and migration. Biomedicines. (2025) 13:339. doi: 10.3390/biomedicines13020339
100. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF - 1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. (2013) 19:1264–72. doi: 10.1038/nm.3337
101. Zhu Z, Cao S, Li H, Zhang Z, Lu Q, Li H, et al. Myeloid-derived suppressor cell-targeted virus-like particles synergistically activate innate immune response for cancer immunotherapy. J Control Release. (2025) 381:113603. doi: 10.1016/j.jconrel.2025.113603
102. Mai Q, Du Q, Zeng F, Chen Y, Wang X, Zou Q, et al. Galectin-3 suppresses CD8(+) T cells function via myeloid-derived suppressor cells recruitment in cervical cancer. Int J Biol Macromol. (2025) 311:143683. doi: 10.1016/j.ijbiomac.2025.143683
103. Lin A, Liang F, Thompson EA, Vono M, Ols S, Lindgren G, et al. Rhesus macaque myeloid-derived suppressor cells demonstrate T cell inhibitory functions and are transiently increased after vaccination. J Immunol. (2018) 200:286–94. doi: 10.4049/jimmunol.1701005
104. Du L, Ji Y, Xin B, Zhang J, Lu LC, Glass CK, et al. Shp2 deficiency in kupffer cells and hepatocytes aggravates hepatocarcinogenesis by recruiting non-kupffer macrophages. Cell Mol Gastroenterol Hepatol. (2023) 15:1351–69. doi: 10.1016/j.jcmgh.2023.02.011
105. Zhao Q, Huang L, Qin G, Qiao Y, Ren F, Shen C, et al. Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL - 6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma. Cancer Lett. (2021) 518:35–48. doi: 10.1016/j.canlet.2021.06.009
106. Domínguez-Romero AN, Esquivel-García CA, Martínez-Cortés F, Martínez-Zarco BA, Odales J, Abraham-Ruiz S, et al. DNA vaccination combined with immune checkpoint inhibition eradicates tumors, inducing life-long immunity against breast cancer in mice. Mol Immunol. (2025) 184:51–63. doi: 10.1016/j.molimm.2025.06.003
107. Zhao Y, Rahmy S, Liu Z, Zhang C, and Lu X. Rational targeting of immunosuppressive neutrophils in cancer. Pharmacol Ther. (2020) 212:107556. doi: 10.1016/j.pharmthera.2020.107556
108. Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. (2016) 76:1367–80. doi: 10.1158/0008-5472.CAN-15-1591
109. Brandau S, Moses K, and Lang S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin Cancer Biol. (2013) 23:171–82. doi: 10.1016/j.semcancer.2013.02.007
110. Liepelt A and Tacke F. Stromal cell-derived factor-1 (SDF - 1) as a target in liver diseases. Am J Physiol Gastrointest Liver Physiol. (2016) 311:G203–209. doi: 10.1152/ajpgi.00193.2016
111. Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. (2018) 24:541–50. doi: 10.1038/s41591-018-0014-x
112. Wang D, Sun H, Wei J, Cen B, and DuBois RN. CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res. (2017) 77:3655–65. doi: 10.1158/0008-5472.CAN-16-3199
113. Lin Q, Ren L, Jian M, Xu P, Li J, Zheng P, et al. The mechanism of the premetastatic niche facilitating colorectal cancer liver metastasis generated from myeloid-derived suppressor cells induced by the S1PR1-STAT3 signaling pathway. Cell Death Dis. (2019) 10:693. doi: 10.1038/s41419-019-1922-5
114. Shen M, Wang YJ, Liu ZH, Chen YW, Liang QK, Li Y, et al. Inhibitory effect of astragalus polysaccharide on premetastatic niche of lung cancer through the S1PR1-STAT3 signaling pathway. Evid Based Complement Alternat Med. (2023) 2023:4010797. doi: 10.1155/2023/4010797
115. Zare E, Yaghoubi SM, Khoshnazar M, Jafari Dargahlou S, Machhar JS, Zheng Z, et al. MicroRNAs in cancer immunology: master regulators of the tumor microenvironment and immune evasion, with therapeutic potential. Cancers (Basel). (2025) 17:2172. doi: 10.3390/cancers17132172
116. Lan T, Gao F, Cai Y, Lv Y, Zhu J, Liu H, et al. The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment. Nat Commun. (2025) 16:333. doi: 10.1038/s41467-024-55577-0
117. Yang Y, Pei T, Liu C, Cao M, Hu X, Yuan J, et al. Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A(+) myeloid cells to promote liver cancer progression. Gut. (2025) 74:255–69. doi: 10.1136/gutjnl-2024-332429
118. Zhao Y, Yu H, Li J, Qian J, Li M, Zhang X, et al. A glucose-enriched lung pre-metastatic niche triggered by matrix stiffness-tuned exosomal miRNAs in hepatocellular carcinoma. Nat Commun. (2025) 16:1736. doi: 10.1038/s41467-025-56878-8
119. Shaha A, Wang Y, Wang X, Wang D, Guinovart D, Liu B, et al. CMTM6 mediates the Warburg effect and promotes the liver metastasis of colorectal cancer. Exp Mol Med. (2024) 56:2002–15. doi: 10.1038/s12276-024-01303-1
120. Piñeiro Fernández J, Luddy KA, Harmon C, and O’Farrelly C. Hepatic tumor microenvironments and effects on NK cell phenotype and function. Int J Mol Sci. (2019) 20:4131. doi: 10.3390/ijms20174131
121. Wang XY, Kazim L, Repasky EA, and Subjeck JR. Immunization with tumor-derived ER chaperone grp170 elicits tumor-specific CD8+ T-cell responses and reduces pulmonary metastatic disease. Int J Cancer. (2003) 105:226–31. doi: 10.1002/ijc.11058
122. Jiang T, Zhang J, Zhao S, Zhang M, Wei Y, Liu X, et al. MCT4: a key player influencing gastric cancer metastasis and participating in the regulation of the metastatic immune microenvironment. J Transl Med. (2025) 23:276. doi: 10.1186/s12967-025-06279-8
123. Bok R, Lee J, Sriram R, Keshari K, Sukumar S, Daneshmandi S, et al. The role of lactate metabolism in prostate cancer progression and metastases revealed by dual-agent hyperpolarized (13)C MRSI. Cancers (Basel). (2019) 11:257.
124. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. (2016) 24:657–71. doi: 10.1016/j.cmet.2016.08.011
125. Tittarelli A, Janji B, Van Moer K, Noman MZ, and Chouaib S. The selective degradation of synaptic connexin 43 protein by hypoxia-induced autophagy impairs natural killer cell-mediated tumor cell killing. J Biol Chem. (2015) 290:23670–9. doi: 10.1074/jbc.M115.651547
126. Xia S, Chen W, Xu Z, Gao Y, Chen J, Ding N, et al. Targeting Dicer reprograms tumor-associated macrophages to promote anti-tumoral immunity in colorectal cancer liver metastasis. J Nanobiotechnol. (2025) 23:421. doi: 10.1186/s12951-025-03518-4
127. Ghosh CC, Cournoyer L, Liu Y, Ballarin A, Layman IB, LaPorte J, et al. Subcutaneous checkpoint inhibition is equivalent to systemic delivery when combined with nelitolimod delivered via pressure-enabled drug delivery for depletion of intrahepatic myeloid-derived suppressor cells and control of liver metastases. J Immunother Cancer. (2024) 12:e008837. doi: 10.1136/jitc-2024-008837
128. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell. (2014) 25:846–59. doi: 10.1016/j.ccr.2014.05.016
129. Lee JH, Chen TW, Hsu CH, Yen YH, Yang JC, Cheng AL, et al. A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors. Invest New Drugs. (2020) 38:99–110. doi: 10.1007/s10637-019-00745-z
130. Cassier PA, Garin G, Eberst L, Delord J-P, Chabaud S, Terret C, et al. MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). Am Soc Clin Oncol. (2019) 37:2579. doi: 10.1200/JCO.2019.37.15_suppl.2579
131. Wolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, et al. Axatilimab in recurrent or refractory chronic graft-versus-host disease. N Engl J Med. (2024) 391:1002–14. doi: 10.1056/NEJMoa2401537
132. Zhu M, Bai L, Liu X, Peng S, Xie Y, Bai H, et al. Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages. J Immunother Cancer. (2022) 10:e005610. doi: 10.1136/jitc-2022-005610
133. Saeed AF. Tumor-associated macrophages: polarization, immunoregulation, and immunotherapy. Cells. (2025) 14:741. doi: 10.3390/cells14100741
134. Fujiwara T, Yakoub MA, Chandler A, Christ AB, Yang G, Ouerfelli O, et al. CSF1/CSF1R signaling inhibitor pexidartinib (PLX3397) reprograms tumor-associated macrophages and stimulates T-cell infiltration in the sarcoma microenvironment. Mol Cancer Ther. (2021) 20:1388–99. doi: 10.1158/1535-7163.MCT-20-0591
135. Chen D, Xiong L, Zhang L, Yu H, Xu Y, Wang M, et al. CSF1R is a prognostic biomarker and correlated with immune cell infiltration in the gastric cancer microenvironment. Pharmgenom Pers Med. (2021) 14:445–57. doi: 10.2147/PGPM.S301303
136. Gu Y, Mi Y, Cao Y, Yu K, Zhang Z, Lian P, et al. The lncRNA MIR181A1HG in extracellular vesicles derived from highly metastatic colorectal cancer cells promotes liver metastasis by remodeling the extracellular matrix and recruiting myeloid-derived suppressor cells. Cell Biosci. (2025) 15:23. doi: 10.1186/s13578-025-01365-2
137. Cai H, Chen Y, Chen X, Sun W, and Li Y. Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2. Cell Immunol. (2023) 384:104642. doi: 10.1016/j.cellimm.2022.104642
138. Lim SY, Yuzhalin AE, Gordon-Weeks AN, and Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. (2016) 7:28697–710. doi: 10.18632/oncotarget.7376
139. Linehan D, Noel MS, Hezel AF, Wang-Gillam A, Eskens F, Sleijfer S, et al. Overall survival in a trial of orally administered CCR2 inhibitor CCX872 in locally advanced/metastatic pancreatic cancer: Correlation with blood monocyte counts. Am Soc Clin Oncol. (2018) 36:92. doi: 10.1200/JCO.2018.36.5_suppl.92
140. Daniel SK, Seo YD, and Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal Malignancies. Semin Cancer Biol. (2020) 65:176–88. doi: 10.1016/j.semcancer.2019.12.007
141. Benedicto A, Romayor I, and Arteta B. CXCR4 receptor blockage reduces the contribution of tumor and stromal cells to the metastatic growth in the liver. Oncol Rep. (2018) 39:2022–30. doi: 10.3892/or.2018.6254
142. D’Alterio C, Buoncervello M, Ieranò C, Napolitano M, Portella L, Rea G, et al. Targeting CXCR4 potentiates anti-PD-1 efficacy modifying the tumor microenvironment and inhibiting neoplastic PD - 1. J Exp Clin Cancer Res. (2019) 38:432. doi: 10.1186/s13046-019-1420-8
143. Hidalgo M, Semenisty V, Bockorny B, Borazanci E, von Hoff D, Feliu J, et al. Bohana-Kashtan OJAoO: A multi-center phase IIA trial to assess the safety and efficacy of BL - 8040 (a CXCR4 inhibitor) in combination with pembrolizumab and chemotherapy in patients with metastatic pancreatic adenocarcinoma (PDAC). Ann Oncol. (2019) 30:xi33. doi: 10.1093/annonc/mdz451
144. Chen L, Xu G, Song X, Zhang L, Chen C, Xiang G, et al. A novel antagonist of the CCL5/CCR5 axis suppresses the tumor growth and metastasis of triple-negative breast cancer by CCR5-YAP1 regulation. Cancer Lett. (2024) 583:216635. doi: 10.1016/j.canlet.2024.216635
145. Huang W, Li W, Chen X, Xiang C, and Luo K. APOE drives glioma progression by modulating CCL5/CCR5 signaling in the tumor microenvironment and inducing M2 macrophage polarization. Immunobiology. (2025) 230:152895. doi: 10.1016/j.imbio.2025.152895
146. Suarez-Carmona M, Chaorentong P, Kather JN, Rothenheber R, Ahmed A, Berthel A, et al. CCR5 status and metastatic progression in colorectal cancer. Oncoimmunology. (2019) 8:e1626193. doi: 10.1080/2162402X.2019.1626193
147. Hawila E, Razon H, Wildbaum G, Blattner C, Sapir Y, Shaked Y, et al. CCR5 directs the mobilization of CD11b(+)Gr1(+)Ly6C(low) polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development. Cell Rep. (2017) 21:2212–22. doi: 10.1016/j.celrep.2017.10.104
148. Yang H, Shao R, Huang H, Wang X, Rong Z, and Lin Y. Engineering macrophages to phagocytose cancer cells by blocking the CD47/SIRPɑ axis. Cancer Med. (2019) 8:4245–53. doi: 10.1002/cam4.2332
149. Michaels AD, Newhook TE, Adair SJ, Morioka S, Goudreau BJ, Nagdas S, et al. CD47 blockade as an adjuvant immunotherapy for resectable pancreatic cancer. Clin Cancer Res. (2018) 24:1415–25. doi: 10.1158/1078-0432.CCR-17-2283
150. Vonderheide RH. CD40 agonist antibodies in cancer immunotherapy. Annu Rev Med. (2020) 71:47–58. doi: 10.1146/annurev-med-062518-045435
151. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. (2011) 331:1612–6. doi: 10.1126/science.1198443
152. Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL, SChad S, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. (2017) 543:428–32. doi: 10.1038/nature21409
153. Maeda A, Digifico E, Andon FT, Mantovani A, and Allavena P. Poly(I:C) stimulation is superior than Imiquimod to induce the antitumoral functional profile of tumor-conditioned macrophages. Eur J Immunol. (2019) 49:801–11. doi: 10.1002/eji.201847888
Keywords: metastatic liver cancer, tumor microenvironment, innate immune cells, adaptive immunity, Kupffer cells, immunotherapy
Citation: Liu D, Li M, Liang Y, Xu F, Li R and Sun Y (2025) Immune microenvironment regulation and clinical immunotherapy strategies of metastatic liver cancer. Front. Immunol. 16:1633315. doi: 10.3389/fimmu.2025.1633315
Received: 22 May 2025; Accepted: 19 August 2025;
Published: 09 September 2025.
Edited by:
Raquel Alarcon Rodriguez, University of Almeria, SpainReviewed by:
Yan-wei Cheng, Henan Provincial People’s Hospital, ChinaHua Ge, First People’s Hospital of Zunyi, China
Copyright © 2025 Liu, Li, Liang, Xu, Li and Sun. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yang Sun, eWFuZ3N1bjc5NUFAMTYzLmNvbQ==