CCL2 orchestrates antitumor immune responses by promoting immune cell recruitment and surveillance. In vitro studies have shown that diverse tumor cell lines chemoattract CD8⁺ and CD4⁺ T lymphocytes through CCL2 secretion (19,20). For example, in a previous study of nude mice, ovarian cancer cells engineered to express CCL2 induced robust monocyte infiltration at the injection site, resulting in localized tumor growth inhibition (20) Clinically, plasma CCL2 levels in patients with pancreatic cancer have been shown to be negatively correlated with tumor proliferation markers (21). In addition, in colorectal cancer preclinical models (22–24), the targeted modulation of tumor-derived chemokines enhances immune cell infiltration and suppresses tumor progression.

CCL2 serves a pivotal role in the metastatic cascade, particularly during epithelial-mesenchymal transition (EMT). Preclinical studies have shown EMT-induced cancer cells upregulate CCL2 expression (22–25), which in turn attracts neutrophils to the TME. While neutrophils are traditionally associated with tumor-promoting inflammation, evidence has highlighted their potential to exert cytotoxic effects against cancer cells in specific contexts (26–28). Tumor-associated neutrophils (TANs) have two phenotypes. ‘N2’ is known as a pro-tumorigenic phenotype, as it exerts a pro-tumorigenic effect at the primary site by secreting oncogenic factors, promoting primary tumor growth and angiogenesis, increasing extracellular matrix degradation and suppressing immune responses (29–33). ‘N1’ is an antitumorigenic phenotype. These neutrophil phenotype switches are contingent on TGF-β signaling, as the neutralization of TGF-β has been shown to induce a shift from ‘N2’ pro-tumorigenic to ‘N1’ antitumorigenic neutrophil states (31). Tumor-entrained neutrophils suppress lung metastatic seeding via H₂O₂-dependent cytotoxic mechanisms, with tumor-derived CCL2 serving as a key mediator of granulocyte colony-stimulating factor-stimulated neutrophil recruitment for optimal anti-metastatic function (28). A preclinical study of mouse breast cancer models further demonstrated that neutrophils accumulate in the lungs prior to the arrival of metastatic cells, establishing a pre-metastatic surveillance niche (28).

TANs exhibit dual roles in cancer progression, with N1-polarized TANs exerting antitumor effects and N2-polarized TANs promoting tumorigenesis. In hepatocellular carcinoma (HCC), cancer-associated fibroblasts (CAFs) secrete cardiotrophin-like cytokine factor 1 (CLCF1), which drives tumor stemness via C-X-C motif chemokine ligand 6/TGF-β and recruits immunosuppressive N2 TANs, forming a pro-tumorigenic feedback loop. Conversely, in lung cancer, C-X-C chemokine receptor type 2 (CXCR2) inhibition shifts TANs toward an N1 phenotype, decreasing immunosuppressive factors (arginase 1, TGF-β) and enhancing CD8⁺ T-cell activity, thereby improving antitumor immunity and chemotherapy response (34,35). These findings highlight TAN polarization as a critical determinant of tumor fate, suggesting therapeutic strategies targeting N2 TANs (such asCLCF1/ERK inhibition in HCC) or promoting N1 TANs (for example via CXCR2 blockade in lung cancer) may modulate the TME.

TILs serve as both prognostic biomarkers in cancer progression and key effectors in immunotherapeutic responses (26). The CCL2/CCR2 signaling axis orchestrates TIL recruitment to the TME, while CCL2 modulates the anti-cancer functions of T lymphocytes and dendritic cells, thereby potentiating antitumor immunity (26).

A previous in vitro study has demonstrated that CCL2 triggers γδ T-cell chemotaxis toward tumor-derived extracts, a process abolished by CCL2-neutralizing antibodies (36). Mechanistic investigation using T-cell receptor Δ chain knockout and CCR2^−/− murine models have revealed that the loss of γδ TILs accelerates tumor progression in vivo, implicating a protective role for the CCR2/CCL2 axis in recruiting antitumor γδ T cells (36). Human tissue analyses (37–39) have further shown that Vδ1⁺ (but not Vδ2⁺) γδ T cells selectively express CCR2 and exhibit CCL2-dependent migration, with CCR2 expression dysregulated across various types of malignancies, including lung, prostate, liver and breast cancer. These findings highlight the tumor-suppressive function of CCL2/CCR2 signaling in orchestrating γδ1 T-cell infiltration, suggesting potential therapeutic strategies targeting Vδ1⁺ subsets in cancer immunotherapy. The natural killer (NK) group 2D receptor is critical for immune surveillance against malignancy (40). In a murine model of metastatic liver cancer, p53 reactivation has been shown to induce CCL2 expression in tumor cells, which is key for robust NK cell recruitment to the TME (41). Mechanistically, p53-mediated CCL2 secretion establishes a chemotactic gradient that enhances NK cell infiltration, thereby facilitating tumor elimination in an NK cell-dependent manner (42). Restoring p53 function in tumor cells also upregulates chemokines with NK cell-recruiting potential, although the antibody-based neutralization of CCL2 abrogates NK cell accumulation in senescent tumors and impairs their clearance, highlighting the role of CCL2 in anti-cancer immunosurveillance (42–45).

Enhanced cell motility and survival are hallmarks of metastatic tumor cells (46). The CCL2/CCR2 signaling pathway governs tumor cell chemotaxis, migratory capacity, survival and proliferation, thereby facilitating oncogenic progression in both hematological malignancies and solid tumors (47–49). The CCL2/CCR2 signaling axis can activate downstream pathways, including the PI3K/AKT, SMAD family member 3, P42/44 MAPK and ERK1/2-MMP2/9 pathways, as well as the protein kinase C-dependent protein tyrosine phosphorylation pathway to affect the proliferation, invasion and infiltration of tumor cells (50–52).

CCL2 promotes chondrosarcoma cell migration by upregulating MMP9 expression and engaging CCR2, thereby inhibiting Ras/Raf-1/MEK/ERK and NFκB signaling cascades (53). In HCC cell model, CCL2/CCR2 engagement triggers focal adhesion kinase tyrosine phosphorylation at Y397, promoting the recruitment of Src family kinases and activation of MMP2/9 through the ERK1/2 signaling cascade (54). Concurrently, calcium ion flux mediated by CCR2 activates the calcineurin-nuclear factor of activated T cells pathway, upregulating MMP9 transcription and enhancing extracellular matrix degradation (55). Sustained CCL2 secretion also polarizes tumor-associated macrophages (TAMs) toward the M2 phenotype, fostering a pro-inflammatory milieu rich in IL-6 and TNF-α that supports cancer cell clonal expansion (56–59). This multifaceted signaling network has been implicated in metastatic progression in multiple types of cancer, including cervical and breast malignancy (56,58). In breast cancer, the CCL2/CCR2 axis regulates cellular motility and survival, thereby driving metastatic dissemination (60,61). Similarly, in prostate cancer, CCL2/CCR2 signaling governs proliferation, apoptosis resistance and invasive potential (62). In bladder cancer, the activation of this axis enhances migration and invasion via protein kinase C activation and tyrosine phosphorylation, independent of its effects on cell proliferation (63). Blockade of CCL2/CCR2 signaling markedly impairs the bone marrow homing of multiple myeloma cells, underscoring its role in hematological malignancy metastasis (64). In nasopharyngeal carcinoma (NPC), CCL2/CCR2 signaling promotes metastasis via ERK1/2-MMP2/9 pathway activation (65). In colorectal cancer, alcohol exposure upregulates CCL2/CCR2 signaling via the glycogen synthase kinase 3β/β-catenin pathway, facilitating metastatic progression (66). Epithelial ovarian cancer exploits CCL2/CCR2 signaling to promote peritoneal dissemination, as demonstrated by the enhanced migration and adhesion of ovarian cancer cells following CCL2 stimulation, a process mediated by the P38 MAPK pathway (67,68).

The CCL2/CCR2 signaling pathway drives the proliferation and migration of acute myeloid leukemia cells, as demonstrated by in vitro and in vivo studies (69). In glioblastoma, tumor-secreted CCL2 orchestrates monocyte recruitment, establishing a pro-tumorigenic microenvironment that fosters neoplastic growth (70). Leveraging this mechanistic insight, preclinical investigation have explored CCR2 antagonists as novel antitumor agents. For example, the pharmacological blockade of CCR2 in lung adenocarcinoma A549 cells attenuates their migratory and invasive capabilities (Fig. 1; Table I) (71).

EMT is the initial step of tumor metastasis, and is involved in the progression and metastasis of various types of cancer (72,73). The CCL2/CCR2 signaling axis promotes EMT in liver cancer through MMP2 (74). There is a growing body of data describing a direct stimulatory effect of CCL2 on tumor epithelial cells (8,75). Notably, interruption of the CCL2/CCR2/STAT3 pathway can inhibit the EMT and migration of prostate cancer cells, inhibiting the progression and metastasis of prostate cancer (75). Furthermore, the TME enhances bladder cancer metastasis by modulating estrogen receptor (ER)β/CCL2/CCR2 EMT/MMP9 signaling following mast cell recruitment (76). The CCL2/CCR2 pathway induces the invasion and EMT of HCC in vitro by activating the Hedgehog pathway (Fig. 2) (77).

Tumor angiogenesis requires the production of angiogenic factors by tumor cells and stromal components. CCL2 directly promotes angiogenesis via the activation of CCR2-expressing vascular endothelial cells (78–80). Concurrently, the CCL2/CCR2 signaling axis enhances vascular permeability, facilitating efficient extravasation of tumor cells and metastatic niche formation (81). Human endothelial cells express CCR2, which promotes tumor angiogenesis and progression after binding to CCL2. Several clinical studies have shown that CCL2 may be a biomarker of tumor angiogenesis (82–84). The activation of the CCL2/CCR2 signaling axis in the TME promotes tumor angiogenesis (83). CCL2 directly interacts with CCR2 on the surface of endothelial cells, resulting in increased vessel sprouting and angiogenesis (84). As a chemokine produced in abundance by certain types of tumor, such as hepatocellular carcinoma (HCC), glioblastoma, and Small Cell Lung Cancer (SCLC) (85), it can also directly promote tumor progression. Therefore, therapy using MCP-1 antagonists in combination with other angiogenesis inhibitors may suppress tumor growth (86).

In contrast to earlier assumptions, emerging evidence has indicated that tumor vascular endothelial cells lack CCR2 expression (87,88). Instead, CCL2 drives angiogenesis indirectly by recruiting TAMs and increasing VEGF-A production in these cells (89–92). In addition, CCL2 enhances cancer cell autonomous VEGF secretion, further contributing to neovascularization. In melanoma, this axis is amplified by autocrine/paracrine loops, wherein CCL2 and its receptor CCR2 are co-expressed (93,94). AM-derived TNFα and IL-1α synergize with VEGF to promote endothelial cell activation, thereby accelerating early-stage tumor angiogenesis and growth (9).

The TME is a dynamically complex ecosystem, where inflammatory networks composed of immune cells and their secretory products influence cancer biology and progression (95). Chemokine-chemokine receptor interactions are key to recruiting inflammatory cells into the TME, with CCL2 serving as a key driver of inflammatory monocyte accumulation (96). Inflammatory monocytes exhibit high expression of CCR2 (26), while other CCR2-expressing leukocytes, including CD8⁺ effector T cells and CD4⁺ regulatory T cells (Tregs) (19,97) and myeloid-derived suppressor cells (MDSCs) (98), are enriched in inflamed tumor tissues. The CCL2/CCR2 pathway orchestrates metastatic microenvironment formation, exerting pro-tumorigenic and pro-metastatic functions in numerous types of cancer (99,100).

In sarcoma and breast cancer, the CCL2/CCR2 axis mediates the recruitment of TAMs and MDSCs to the TME (89). T cells infiltrate tumors in an antigen-specific manner, with IFN-γ secreted by early-invading T cells inducing tissue macrophages to increase CCL2 expression (101,102). This creates a positive feedback loop wherein CCL2 recruits additional T cells and macrophages via CCR2 signaling, enhancing immune cell infiltration. CCR2 expression is detectable in tumor-infiltrating immune cells, supporting the role of active chemotactic recruitment (101,102). In NPC, this mechanism is exemplified by T cell-derived IFN-γ activating macrophages to secrete CCL2, thereby amplifying T-cell and macrophage accumulation via the CCL2/CCR2 pathway (103).

CAFs, as a key component of the TME, represent activated fibroblast populations that impact stromal compartment remodeling within the TME via collagen deposition and MMP secretion (104). CAFs constitute one of the most prevalent cell types in the tumor stroma (105), and evidence has highlighted their tumor-promoting functions, including accelerating tumor proliferation, facilitating metastatic progression and shielding tumors from therapeutic agent penetration (106–108).

Accumulating evidence has highlighted the crosstalk between CAFs and immunosuppressive cell lineages, which is primarily due to the immune-modulatory functions of CAFs (109–111). CAFs secreting CCL2 facilitate the recruitment of CCR2⁺ monocytes from the bloodstream into the TME, where direct cell-cell interactions drive monocyte differentiation into MDSCs. CAF-educated MDSCs suppress T-cell proliferation via upregulation of NADPH oxidase 2 and indoleamine 2,3-dioxygenase 1, leading to excessive reactive oxygen species production that inhibits immune effector function (Fig. 3) (112).

Crosstalk with cancer cells drives CCL2 upregulation in CAFs, which contributes to metastatic niche establishment during early tumor progression and modulates broader tumor functionality (113–118). In a murine liver tumor model, fibroblast STAT3/CCL2 signaling has been shown to enhance MDSC recruitment, thereby promoting tumor growth (119). In addition, the CCL2/CCR2 signaling pathway facilitates early breast cancer survival and invasion via a fibroblast-mediated mechanism (120).

A previous study demonstrated that discoidin domain receptor 1 (DDR1) orchestrates an immunosuppressive TME by activating CAFs to secrete CCL2 and IL-6. This signaling axis exhibits dual regulatory effects by recruiting immunosuppressive cells, including MDSCs and TAMs, and facilitating extracellular matrix remodeling through enhanced collagen deposition and MMP9 activation. These findings demonstrate the key role of the DDR1/CCL2/IL-6 pathway in CAF-mediated immunosuppression, providing a potential therapeutic strategy to target tumor fibrosis and immune evasion (121,122).

CCL2 primarily regulates the directional migration and invasive infiltration of reticuloendothelial system cells, with a focus on monocyte/macrophage phenotypes (123). CCL2 induces monocytes to exit the bloodstream and extravasate into peripheral tissue (71), where they differentiate into tissue-resident macrophages. The CCL2/CCR2 signaling pathway has been implicated in recruiting macrophages in various types of human cancer, including those originating in the bladder, cervix, ovary, lung and breast (124–127). TAMs, a major component of infiltrating inflammatory cells, are regulated by the CCL2/CCR2 pathway through a macrophage-dependent mechanism sustained by positive feedback loops (61,128). As a key chemokine system mediating blood cell recruitment, particularly macrophages, into tissues (11,128–130), CCL2/CCR2 signaling drives tumor progression. M2-polarized TAMs influence tumor progression and metastasis (131), and CCL2 secretion recruits TAMs that mediate metastatic phenotypes in ER-negative breast cancer (64).

TAMs drive prostate cancer metastasis via activation of the CCL2/CCR2 signaling pathway (132). Phenotypically, tumor-infiltrating macrophages can be tumor-supportive (M2) or function in tumor immune surveillance (M1). TAMs of the M1 type lead to a better prognosis, whereas TAMs of the M2 type lead to a poorer prognosis. Tumors associated with M2-type TAMs include breast, ovarian and prostate cancer (133–135). TAM recruitment is dependent on the CCL2/CCR2 signaling axis and the formation of a tumor-supportive microenvironment depends on altered cellular dynamics following the interaction of CCL2, T cells and monocytes (136).

TAMs serve a pivotal role in driving hormone resistance in prostate cancer cells (137). Within the prostate TME, M2-polarized TAMs exert pro-tumorigenic effects. Previous studies (78,138) employed a PC3 cell xenograft model to show that CCL2 increases in vivo prostate tumor growth and metastasis by enhancing TAM recruitment and angiogenesis. Investigations (139,140) have also revealed that M2-phenotype TAMs influence cancer progression and metastasis; in human lung cancer, CCL2/CCR2 signaling promotes tumor cell proliferation, migration and M2 polarization of TAMs (131). In pancreatic ductal adenocarcinoma, the CCL2/CCR2 axis recruits TAMs to establish an immunosuppressive TME (141). Conversely, anti-CCL2 antibody treatment in breast cancer xenograft models has been shown to diminish macrophage infiltration and tumor growth (142,143).

The CCL2/CCR2 pathway is indispensable for monocyte/macrophage recruitment. The therapeutic interruption of this pathway suppresses inflammatory monocyte recruitment, TAM infiltration and M2 polarization, thereby reversing the immunosuppressive state of the TME and activating antitumor CD8⁺ T-cell responses (39). Platelet-derived growth factor-BB-mediated autocrine signaling drives CCL2 secretion, which recruits macrophages via the CCL2/CCR2 axis to facilitate lung cancer cell invasion (144). Targeting CCL2/CCR2 signaling in tumor-infiltrating macrophages has emerged as a promising therapeutic strategy for HCC (145). Preclinical studies (26,93,146,147) have also shown that genetic knockout of CCR2 or pharmacological blockade with CCR2 antagonists inhibits malignant growth and metastasis, decreases postoperative recurrence and improves survival rates. In pancreatic adenocarcinoma, cancer cells exploit chemokine pathways, particularly CCL2/CCR2, to establish an immunosuppressive niche (146). Blocking TAM recruitment inhibits murine breast cancer growth (148). In addition, the JAK2/STAT3 signaling pathway promotes M2-like macrophage polarization, which drives gastric cancer metastasis via EMT (149).

Tregs, a specialized subset of T cells, are key for maintaining peripheral self-tolerance and preventing immunopathological responses (150). Tumors exploit immune evasion mechanisms to sustain uncontrolled growth, with high intratumoral Treg abundance contributing to the establishment of immunosuppressive microenvironments. Tregs exert suppressive effects on T-cell proliferation and cytotoxic function (151,152). The infiltration of Tregs in tumors is influenced by both in situ generation (mediated by cytokine secretion) and peripheral recruitment (driven by chemokine signaling) (153). Tumor-derived CCL2 has been implicated in inducing Treg migration into the TME. For example, in glioma local immunosuppression is enhanced by selectively recruiting CCL2/CCR2-dependent Tregs (129), while colorectal cancer cells secrete CCL2 that binds to CCR2 on cytotoxic T lymphocytes (CTLs), paradoxically promoting CTL migration to tumors (44).

Tumors employ diverse evasion strategies to circumvent immune recognition and elimination. Intratumoral immunosuppressive MDSCs represent a heterogeneous population of immature myeloid cells originating from bone marrow progenitors (154–156). MDSCs exert multifaceted tumor-promoting activities (157). The CCL2/CCR2 signaling pathway governs the recruitment of myelosuppressive cells to tumor sites. Studies have demonstrated that CCR2 is universally expressed on MDSCs, the primary drivers of tumor immune evasion, and blocking CCL2/CCR2 signaling inhibits MDSC migration and tumor growth facilitated by these cells (31,112,158–160). Collectively, these data demonstrate a key role for the CCL2/CCR2 pathway in regulating MDSC trafficking. CCL2/CCR2 interactions also recruit other immunosuppressive cells, including monocytes, to form a pro-metastatic microenvironment (26,98).

The immunosuppressive Treg-MDSC network drives immune exclusion and immune checkpoint inhibitor (ICI) resistance. In head and neck squamous cell carcinoma, semaphorin (SEMA)4D blockade using pepinemab disrupts MDSC recruitment while enhancing T-cell infiltration (KEYNOTE-B84 trial) (161). In bladder cancer, gemcitabine/BCG decreases IL-6-mediated MDSC suppression. Prostate cancer subtyping has revealed TGF-β-enriched, immune-excluded tumors (stage I) with a poor ICI response vs. inflamed subtypes (S-IV). Targeting this axis (via SEMA4D inhibition or myeloid modulation) represents a promising therapeutic strategy (162).