European Journal of Gynaecological Oncology,2025,46(11):1-10 DOI:10.22514/ejgo.2025.133
Review
A new concept for oncogenic analysis of tumor microenvironment and chemokines and non-coding RNAs in breast cancer
Jianli Li1, Shaofeng Yang1, Xing Li1,*,

1Department of Thyroid Breast Surgery, Affiliated Hospital of Inner Mongolia Medical University, Inner Mongolia Medical University, 010050 Hohhot, Inner Mongolia Autonomous Region, China

*Corresponding Author(s):gxfabc2024@163.com (Xing Li)

History Submitted: 17 April 2025 | Accepted: 21 May 2025 | Published: 15 November 2025
Copyright:  ©2025  The Author(s). Published by MRE Press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Breast cancer (BC) remains a leading malignancy affecting women globally, with surgery combined with chemotherapy constituting the primary therapeutic strategy. However, not all BCs present identifiable chemotherapy targets, and conventional chemotherapy approaches often demonstrate limited efficacy. The discovery of novel therapeutic avenues has spotlighted chemokines, a family of small molecular-weight proteins that govern immune cell migration and localization by interacting with specific receptors. In the context of BC, chemokines are implicated not only in cellular trafficking but also in facilitating tumor progression by modulating immune responses, promoting angiogenesis and remodeling stromal components within the tumor microenvironment (TME). Moreover, various cellular and molecular factors exert regulatory effects via chemokine signaling, with notable crosstalk observed between chemokine pathways, upstream and downstream non-coding RNAs (ncRNAs), and other signaling cascades. This review systematically delineates the functional roles of chemokines and ncRNAs within the BC TME, synthesizes insights from multiple signaling pathways, and performs a multimodal analysis integrating these elements, aiming to inspire novel strategies for BC treatment.

Keywords:Tumour microenvironment (TME);Breast cancer;Immune modulation;Targeted therapy;Chemokines
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Cite this article

Jianli Li, Shaofeng Yang, Xing Li. A new concept for oncogenic analysis of tumor microenvironment and chemokines and non-coding RNAs in breast cancer.European Journal of Gynaecological Oncology,2025,46(11):1-10 DOI:10.22514/ejgo.2025.133

1. Introduction

Chemokines, an essential category of signaling molecules, play a crucial role in directing immune cell movement and localization, demonstrating complex and varied functions within the BC TME. The TME consists of various components, including tumor cells, immune cells like tumor-associated macrophages (TAMs) and regulatory T cells, as well as stromal cells such as fibroblasts and the extracellular matrix (ECM). Together, these elements form a complex and dynamic network that exhibits both immunosuppressive and tumor-promoting functions [1, 2, 3]. By interacting with particular G protein-coupled receptors (GPCRs), chemokines play a crucial role in the recruitment and polarization of immune cells, while also exerting direct effects on tumor cell proliferation, angiogenesis and matrix remodeling [4, 5, 6]. For example, the CXCL12/CXCR4 axis has been demonstrated to facilitate the migration of BC cells and promote distant metastasis through the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways [7, 8, 9]. Conversely, the CCL2/CCR2 axis promotes an immunosuppressive microenvironment by recruiting M2-polarized TAMs [10, 11], thereby dampening anti-tumor immune responses. Recent findings indicate that aberrations in chemokine networks correlate strongly with therapeutic resistance, immune evasion and unfavorable prognosis in BC, underscoring their potential as therapeutic targets [12, 13]. Nevertheless, the substantial heterogeneity of the TME and the pleiotropic functions of chemokines present significant challenges for the development of effective targeted interventions [14, 15]. Emerging evidence also emphasizes the critical association between the TME and key clinical outcomes, including cancer progression, metastasis, prognosis and treatment efficacy [16]. Among TME components, macrophages are increasingly recognized as determinants of solid tumor progression owing to their remarkable plasticity and heterogeneity. Strategies aimed at targeting and reprogramming macrophages toward anti-tumor phenotypes have thus garnered considerable attention as innovative approaches in cancer immunotherapy [17]. This review integrates current insights into the roles of chemokines, macrophages and ncRNAs within the BC TME, elucidating their individual and interconnected functions, and highlighting their collective influence on tumor biology and therapeutic potential.

2. Basic concepts of chemokines and their receptors

Chemokines represent a group of small molecular-weight proteins, generally falling within the range of 8 to 15 kDa, with around 50 unique members recognized in mammals [18]. According to the quantity and arrangement of conserved N-terminal cysteine residues, chemokines are classified into four primary subfamilies: CC, CXC, CX3C and C chemokines. The CC subfamily, which includes CCL1 to CCL28, constitutes the most extensive group, demonstrating significant chemotactic activity across diverse leukocyte populations. In contrast, the CXC subfamily, encompassing CXCL1 to CXCL16, is characterized by a smaller number of members and is further categorized based on the presence or absence of a specific amino acid motif consisting of glutamate, leucine and arginine (the ELR motif). CXC chemokines bearing the ELR motif (ELR+) are typically pro-angiogenic, directly activating endothelial cells (ECs) to stimulate neovascularization, whereas ELR− CXC chemokines generally inhibit angiogenesis within tumors. The C chemokine family is represented by XCL1 and XCL2, while the CX3C family currently consists of a single member, CX3CL1 [19]. Classical chemokine receptors are part of the seven-transmembrane GPCR superfamily and facilitate cellular migration via G protein signaling pathways. Atypical chemokine receptors, unlike their conventional counterparts that signal through G proteins, promote cell migration through different mechanisms [20, 21]. These atypical receptors contribute to the regulation of chemokine gradients by scavenging excess chemokines and can suppress inflammatory responses in a G protein-independent manner [4, 22]. To date, approximately 20 distinct chemokine receptors have been characterized and can be classified into four groups based on their ligand specificity: CCR and CC chemokine receptors, as well as CXCR and CXC chemokine receptors. Notably, CC and CXC chemokines are the predominant subfamilies expressed within the TME, where they have been extensively implicated in regulating tumor progression, inflammation, immune modulation and metastatic dissemination [23, 24].

3. Composition and characteristics of the BC TME

The TME consists of malignant cells, as well as non-malignant cellular components such as immune and stromal cells, along with the ECM [25, 26]. The intricate interactions between tumor cells and their surrounding microenvironment play a crucial role in determining tumor progression and the effectiveness of treatments. Within the BC TME, the non-malignant cellular components encompass a diverse array of immune cells. Additionally, stromal elements such as ECs and adipocytes are present [27]. Neoplastic cells, along with tumour-associated macrophages and stromal cells, play a significant role in the phenomenon of T cell exhaustion by enhancing the expression of co-inhibitory receptors. Furthermore, regulatory T cells (Tregs) release immunosuppressive cytokines that impede the activity of tumor-specific cytotoxic T lymphocytes (CTLs). Concurrently, TAMs facilitate tumor growth, invasion, and angiogenesis by upregulating Programmed cell death ligand 1 (PD-L1) expression on cancer cells [2, 28]. Considering these mechanisms, the strategy of targeting and reversing the immunosuppressive characteristics of the TME is viewed as a promising avenue for anti-tumor therapies. Tumour infiltrating lymphocytes (TILs) are immune cells that move into malignant tissues, contributing significantly to the host’s immune response and aiding in the process of tumor elimination. Conversely, the immunosuppressive cell populations present in the BC TME, contribute to the advancement of tumor growth and the spread of metastases. Stromal components, including fibroblasts, vascular ECs, and mesenchymal stromal cells (MSCs), play a crucial role in the processes of tumor growth, invasion and metastasis [29]. Natural killer (NK) cells are acknowledged for their crucial function in immune surveillance and the inhibition of metastatic dissemination in BC [30]. Beyond cellular components, the ECM serves a pivotal function in BC development. It not only provides mechanical support but also directs cellular behavior through biomechanical signaling [31]. Cellular adaptation to ECM-derived forces can, in turn, remodel the surrounding microenvironment. ECM stiffness, a key physical property, profoundly impacts BC cell proliferation, metastatic potential, and responsiveness to chemotherapy [32]. Furthermore, the arrangement of the ECM, especially the alignment of collagen fibers, has been demonstrated to enhance the migration of invasive BC cells more efficiently compared to their non-invasive counterparts [33, 34]. Beyond its mechanical and structural properties, the biochemical makeup of the ECM significantly impacts the progression of breast tumors, the formation of metastatic niches, and the growth of metastases. Growing evidence underscores the essential functional roles of various ECM proteins in facilitating BC development and augmenting metastatic progression [35]. As Table 1.

Table 1.Summary tables to concisely present key findings chemokine axes, associated signaling pathways.
ChemokinesSignal wayPlay a role
CCL20
PKC (protein kinase C)Promotes stem cell self and maintenance
NF-κB (nuclear factor kappa-B)Promotes drug efflux
CXCL8
PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B)Promote the proliferation and migration of tumor cells
STAT3/mTOR (Signal Transducers and Activators of Transcription 3/Mammalian Target of Rapamycin)Inhibits T cell activation
CCL5PI3K/AKT/mTORPromotes cell proliferation
CXCL11MAPK/ERK (mitogen-activated protein kinase/extracellular regulated protein kinases)Promote cell proliferation, migration and invasive activity
CCL21/CCR7TGF-β (transforming growth factor-β)Increases anti-tumor immunity

4. Role of chemokines in the BC TME

BC represents the most prevalent malignancy among women worldwide [36]. Utilizing the expression profiles of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67, BCs are categorized into specific molecular subtypes. Among these, triple-negative breast cancer (TNBC), defined by the lack of ER, PR and HER2 expression, is linked to a notably unfavorable prognosis (Fig. 1).

The picture illustrates the interplay between different chemokines and the different ways in which they act to cause breast cancer. PKC: protein kinase C; NF-κB: nuclear factor kappa-B; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; IGF-1: insulin-like growth factor 1; PD-L1: Programmed cell death ligand 1; ERK: extracellular regulated protein kinases; BCL-2: B-cell lymphoma-2; VEGF: vascular endothelial growth factor; GLUT1: glucose transporters1.

Fig. 1.The picture illustrates the interplay between different chemokines and the different ways in which they act to cause breast cancer. PKC: protein kinase C; NF-κB: nuclear factor kappa-B; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; IGF-1: insulin-like growth factor 1; PD-L1: Programmed cell death ligand 1; ERK: extracellular regulated protein kinases; BCL-2: B-cell lymphoma-2; VEGF: vascular endothelial growth factor; GLUT1: glucose transporters1.

4.1 CCL2 and BC

Emerging evidence has implicated CCL2 as a key factor associated with unfavorable outcomes in BC. CCL2 has been recognized as a significant chemokine in various malignancies, where it plays a role in the recruitment of myeloid-derived suppressor cells (MDSCs) into tumor tissues [37, 38]. The presence of CCL2, originating from tumors, plays a crucial role in attracting monocytes to the TME, thereby enhancing their transformation into TAMs [39]. Furthermore, CCL2 derived from TAMs, along with vascular endothelial growth factor (VEGF), promotes angiogenesis, facilitating the growth of new tumor cells in proximity to the newly formed blood vessels. These newly formed epithelial tumor cells can, in turn, express and secrete CCL2, establishing a positive feedback loop. In addition, CCL2 secreted by cancer cells activates downstream effectors that promote BC cell extravasation, colonization, and metastatic spread. Furthermore, monocyte chemotactic protein-1 (MCP-1), through its receptor CCR2, exerts direct protumorigenic effects, thereby further driving disease progression [40].

4.2 CCL20 and BC

Elevated expression levels of CCL20 have been associated with reduced overall survival (OS) and metastasis-free survival (MFS) in patients with BC. Experimental investigations have shown that the intraperitoneal delivery of an anti-CCL20 antibody effectively inhibited osteolytic bone metastasis in murine models. Concurrently, CCL20 markedly increased the invasive potential and stimulated the secretion of matrix metalloproteinases (MMP)-2 and -9 in TNBC cell lines [41]. Chemoresistance continues to pose a significant obstacle in the management of triple-negative BC. CCL20 operates by activating the nuclear factor p65 via the protein kinase C and p38 mitogen-activated protein kinase pathway, thereby promoting the self-renewal and sustenance of BC stem cells and stem-like populations. Moreover, the activation of nuclear factor kappa-B (NF-κB) signaling induced by CCL20 leads to the upregulation of multidrug resistance protein 1, which enhances the efflux of paclitaxel and contributes to the development of therapeutic resistance [42]. The results indicate that focusing on CCL20 or its associated pathways may offer a viable approach to address chemoresistance in BC [42]. Although CCL20 has been shown to modulate the TME via activation of NF-κB and other pathways, a direct causal link between CCL20-mediated TME remodeling and breast cancer stem cells (BCSC)-driven tumor progression remains to be conclusively established. Recent studies have demonstrated that CCL20 facilitates the proliferation of polymorphonuclear (PMN)-MDSCs throughout the bone marrow (BM) [43], bloodstream, spleen and TMEs. CCL20 interacts with its receptor CCR6, promoting the differentiation of granulocyte-monocyte progenitors (GMPs) into granulocytic precursors (GPs), which enhances the expansion of PMN-MDSCs and strengthens an immunosuppressive TME [43, 44].

4.3 CCL8 and BC

Within the TME, cancer-associated adipocytes (CAAs) play a significant role in tumor progression, particularly through the secretion of CXCL8, a key cytokine that affects the immunosuppressive landscape. CXCL8 functions as a pro-inflammatory chemokine and serves as a strong chemoattractant for myeloid cells, often linked to unfavorable clinical outcomes in cancer patients [45]. In BC, especially in triple-negative BC, cancer-associated adipocytes-derived CXCL8 facilitates tumor cell proliferation, migration, invasion, Epithelial-mesenchymal transition (EMT) and lung metastasis through the activation of the PI3K/AKT pathway [46]. Furthermore, CAAs have the capacity to suppress T cell activation by promoting the expression of CD274 (PD-L1) via mechanisms mediated by CXCL8. CXCL8 modulates PD-L1 expression by influencing c-Myc through the Signal Transducers and Activators of Transcription 3 (STAT3)/Mammalian Target of Rapamycin (mTOR) pathway, which results in diminished T-cell infiltration and facilitates immune evasion. These findings suggest that targeting the CAA-CXCL8 axis may offer novel therapeutic opportunities for treating TNBC [46, 47, 48, 49].

4.4 CCL5 and BC

Recent studies have underscored the crucial function of CCL5 in the progression of BC. In normal breast ducts and benign lesions, the expression of CCL5 in epithelial cells is minimal; however, there is a marked increase in its production during the process of malignant transformation. Increased levels of CCL5 in tumors and their surrounding microenvironment stimulate the PI3K/AKT/mTOR pathway, which facilitates resistance to growth suppression and the avoidance of programmed cell death. Furthermore, the insulin-like growth factor 1 (IGF-1) pathway, recognized as a significant oncogenic driver, enhances tumor invasion and progression. Increased CCL5 expression enhances glucose　transporters1 (GLUT1) levels on tumor cells, providing metabolic support necessary for sustained proliferation and angiogenesis. Cytokines such as interleukin (IL)-6 and aberrations in HER2—phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling further upregulate CCL5, amplifying tumorigenesis. Moreover, expression of the CCR5 receptor, the cognate receptor for CCL5, is markedly higher in BC tissues compared to normal counterparts. CCR5 expression correlates with enhanced cell motility, invasiveness and tumor-forming capabilities in murine models, particularly through elevated DNA repair gene expression. High CCR5 levels also facilitate improved DNA repair following genotoxic stress [50, 51, 52, 53]. Furthermore, elevated plasma CCL5 concentrations in BC patients have been associated with upregulated CX3CL1 expression, which stimulates tumor proliferation via the epidermal growth factor signaling cascade and promotes EMT [7]. BM-derived CCL5 has also been implicated in enhancing TNBC growth by regulating MDSC expansion, suggesting a mechanism by which CCL5 promotes immune evasion and tumor progression [54, 55]. Hypoxia, a critical factor in tumor progression, further exacerbates these effects. Overexpression of CCR5 has been shown to enhance hypoxia-induced migration, whereas CCR5 knockdown attenuates this response. Clinical samples demonstrate that elevated levels of hypoxia-inducible factor 1 (HIF-1) mRNA are associated with increased expression of CCR5 and CCL5, suggesting a potential regulatory role of HIF-1 on this chemokine-receptor axis in hypoxic environments. Furthermore, CCL5, in conjunction with tumor-derived colony-stimulating factors, promotes the production of MDSCs in the BM, thereby facilitating the progression of BC [19, 56, 57, 58, 59].

4.5 CCL19 and BC

Emerging data indicate that dendritic cells (DCs) that produce CCL19 are linked to improved anti-tumor immune responses and positive outcomes in BC patients undergoing anti-PD-(L)1 immunotherapy. In TNBC, the varying levels of CCL19-expressing dendritic cells highlight their essential role in stimulating the immune response. The engagement of CCL19 produced by dendritic cells with T cells that express CCR7 amplifies immune responses mediated by PD-1 [60, 61]. CCL19 enhances the immunological response in triple-negative BC by promoting the proliferation of CCR7+ CD8+ T cells, especially a CCR7+ TCF-1+ CD8+ subset that exhibits both memory-like and stem-like characteristics, which play a crucial role in the effectiveness of checkpoint blockade therapies. In a similar vein, the intratumoral administration of CCL21, which utilizes CCR7 as a receptor in common with CCL19, has shown to augment CD8+ T cell cytotoxicity and enhance responses to anti-PD-(L)1 therapy in various solid tumors [62, 63, 64, 65, 66, 67]. Furthermore, CXCL11 has been demonstrated to enhance the proliferation, migration, and invasiveness of MDA-MB-231 BC cells via the activation of the extracellular regulated protein kinases (ERK) pathway, which plays a vital role in regulating cell survival, proliferation and gene expression [68].

4.6 CXCL11/CXCR3 and BC

CXCL11 demonstrates pro-tumorigenic effects in BC through its interaction with the CXCR3 receptor, subsequently activating the ERK pathway. This activation promotes the advancement of the cell cycle by increasing the levels of proteins that regulate the cell cycle [69, 70]. In addition to its role in promoting cell proliferation, CXCL11 contributes to cell survival by increasing the expression of anti-apoptotic proteins through ERK-mediated pathways. This mechanism effectively inhibits apoptosis, thereby supporting tumor growth [71, 72].

4.7 CCL8, CCL21 and BC

Both CCL8 and CCL21 are emerging as potential prognostic markers in BC [73]. CCL8, in particular, has been shown to stimulate fibroblast activation in subsets of TNBC, with its expression correlating with an increased risk of metastatic recurrence [24]. Maintenance of a CCL8 gradient within breast epithelial and stromal tissues appears critical for promoting metastasis. Disruption of CCL8 signaling influences tumor histopathology and promotes cellular processes such as endocytosis, exocytosis and dissemination [74]. CCL8 thus contributes to BC progression by remodeling the TME through both autocrine and paracrine mechanisms. The functional impact of CCL21 on tumor progression, meanwhile, varies depending on the expression patterns of CCL21 and its receptor CCR7 within distinct cellular compartments. For instance, CCL21 enhances CCR7 activation, driving dendritic cell maturation and modulating anti-tumor immune responses [75].

4.8 CCR4 and BC

In BC, tumor-derived transforming growth factor β (TGFβ), in conjunction with sustained T cell receptor (TCR) stimulation, encourages the acquired expression of FOXP3 (recombinant protein) in CD4+ CD25-T cells, thereby aiding their differentiation into regulatory T (Treg) cells [76]. The TGFβ/TCR signaling pathway inhibits the interaction of DNA methyltransferase-1 with the FOXP3 promoter, thereby maintaining FOXP3 expression in Tregs. The results of our study indicate that TGFβ-induced FOXP3 plays a crucial role in augmenting CCR4 transcription, thereby facilitating the effective infiltration of Tregs into TMEs. In contrast, the removal of FOXP3 leads to a decrease in the population of CCR4+ Tregs and impairs their migration to tumor sites, which subsequently boosts anti-tumor immune responses and restricts tumor proliferation. Translational studies utilizing in vivo tumor models have demonstrated that altering the expression of CCR4 or FOXP3 can markedly enhance the effectiveness of chemotherapy and immunotherapy in BC patients [77]. The examination of chemokines and their corresponding ligands uncovers a consistent phenomenon: in addition to their immediate impacts on the TME, numerous chemokines influence BC cell proliferation, migration and apoptosis via various signaling pathways, whether directly or indirectly. This raises key questions regarding causality—whether chemokine-mediated alterations in the TME drive tumor initiation, or whether primary changes in signaling pathways lead to TME remodeling during tumor development. Clarifying whether chemokines act as initiators or effectors of TME alterations remains a critical avenue for future investigation.

5. Chemokines and TME in the treatment of BC

Beyond the therapeutic implications discussed above, several chemokines have demonstrated direct potential as therapeutic targets in BC. For example, CCL25 provides a survival benefit to BC cells by blocking cisplatin-induced apoptosis through CCR9 via a PI3K-dependent mechanism, while concurrently activating cell survival pathways that involve AKT [78]. Acharyya et al. [79] described a feedback mechanism that connects chemotherapy-induced chemoresistance with the production of chemokines [62]. In particular, CXCL1 and CXCL2 attract CD11b+ GR1+ (A fluorescent marker) myeloid cells, which then release supplementary factors, such as S100A8/9, thereby enhancing the survival of cancer cells. While chemotherapy effectively leads to the death of tumor cells, it concurrently triggers the production of Tumor Necrosis Factor (TNF-α) from both endothelial and stromal cells. This process results in the upregulation of CXCL1 and CXCL2 within cancer cells, thereby enhancing the CXCL1/2–S100A8/9 axis and playing a role in the development of chemoresistance [79]. Notably, inhibition of CXCR2 has been shown to disrupt this chemokine-driven resistance circuit, thereby enhancing the efficacy of chemotherapy [79]. As previously discussed, CCL5 promotes cancer cell invasiveness via CCR5 signaling. In preclinical BC models, administration of CCR5 antagonists reduced basal-like BC cell invasion and lung metastases in vitro, suggesting that CCR5 blockade may serve as an effective adjuvant strategy for this aggressive subtype [51]. Additionally, chemotherapy-induced CXCL8 upregulation in damaged cells increases tumor cell survival and self-renewal capacity. Inhibition of CXCL8 receptors CXCR1 and CXCR2 has therefore surfaced as a potentially beneficial complementary approach to mitigate tumor recurrence [80, 81]. The CXCL12-CXCR4 axis, due to its pivotal involvement in metastasis, has been approached through the use of CXCR4 antagonists to impede tumor spread [82]. Moreover, CCL19 and CCL21, which regulate dendritic cell and T lymphocyte interactions within lymph nodes, are increasingly recognized as natural immune adjuvants, enhancing antitumor immune responses [83, 84].

6. Immunosuppressive chemokine cell signaling and TME

Chemokine concentration gradients exert profound influences on the TME. Pro-tumorigenic chemokines attract immunosuppressive immune cells, promoting tumor progression, while anti-tumorigenic chemokine gradients facilitate the recruitment of effector immune cells, enhancing anti-tumor immunity. In this section, we discuss the critical crosstalk between key chemokines and immune regulation within the TME.

6.1 TAMs: the CCR2-CCL2 and CCR5-CCL5 signaling axes

TAMs, essential elements of the TME, primarily display immunosuppressive and tumor-enhancing functions [85]. The CCR2-CCL2 signaling pathway plays a vital role in the recruitment of TAMs and MDSCs to the TME. Simultaneously, the CCL5-CCR5 pathway facilitates the movement of TAMs, MDSCs and Treg cells. Interfering with the CCL5-CCR5 signaling pathway has demonstrated an ability to hinder the recruitment of these immunosuppressive cell populations, consequently leading to a reduction in tumor growth [86, 87].

6.2 Regulatory T cell migration to the CCR4-CCL22/17 axis in TME

The CCR4-CCL17 signaling pathway promotes the movement of CCR4+ T cells, particularly Th2 and Treg cells, contributing to an immunosuppressive TME. CCL22, an additional ligand for CCR4, likewise promotes the migration of Treg cells. In BC, the CCR4-CCL22 axis plays a significant role in fostering the accumulation of Tregs within the TME, which in turn contributes to the exclusion of effector T cells and aids in immune evasion [88, 89, 90].

6.3 Dendritic cells migrate into the TME through the CCR5-CCL5 and CCR6-CCL20 signaling pathways

A chemokine gradient formed by CCL3, CCL4 and CCL5 recruits dendritic cells (DCs) into the TME. The CXCR3 ligands secreted by infiltrating DCs play a vital role in attracting effector CD8+ T cells to the tumor. Additionally, the CCR6-CCL20 axis is instrumental in directing DC migration to sites of inflammation, with CCL20 facilitating DC recruitment into tumor tissues [91].

The migration of inflammatory factors and immunosuppressive cells within the TME via chemokines raises an important question: could other biological substances also utilize chemokine-mediated pathways to achieve their functional goals? Moreover, the complexity of chemokine signaling networks suggests the possibility of crosstalk or interference among different pathways, potentially contributing to tumorigenesis. Disruption or mismatch between chemokine-mediated signaling and cellular pathways could represent an underappreciated cancer-promoting mechanism. Furthermore, interactions between chemokine pathways and canonical oncogenic signaling cascades warrant critical examination. Given that microRNAs (miRNAs) regulate the upstream elements of both the PI3K/AKT and Janus Kinase (JAK)/STAT pathways, it is plausible to hypothesize that miRNAs might also modulate chemokine signaling directly or indirectly. Thus, expanding our understanding of the regulatory network—from microRNA and circular RNA (circRNA) regulation to JAK/STAT activation, chemokine expression, downstream target gene modulation, and consequent TME remodeling—may uncover a complex but critical signaling axis essential to tumor progression. Future research should focus on elucidating the upstream alterations driven by miRNAs, with the goal of controlling downstream cascade events to ultimately regulate tumorigenesis and cancer development.

7. The interaction between chemokines and non-coding RNAs

Growing evidence indicates that various microRNAs (miRNAs) play a significant role in the modulation of chemokine expression, especially in the downregulation of CXCL1 levels. A decrease in miRNA expression frequently results in the overexpression of CXCL1, which in turn may facilitate tumor progression [92]. Alterations in miRNA profiles could also be fundamental to the mechanisms of specific anticancer agents. For example, curcumin has demonstrated the ability to enhance the expression of miR-181b in BC cells, which subsequently leads to the direct downregulation of CXCL1, highlighting one of the principal anticancer mechanisms attributed to curcumin [93]. CXCR4 has been identified as a significant therapeutic target, with its knockdown through intracellular siRNA delivery demonstrating effective inhibition of tumor growth. In the MDA-MB-231 BC cell line, the silencing of CXCR4 resulted in a notable decrease in tumor progression [94]. Inflammatory mediators serve as downstream targets of non-coding RNAs [94]. In contrast, LINC00330 plays a crucial role in inhibiting tumor progression by interfering with the CCL2/CCR2 axis and its downstream PI3K/AKT pathway through autocrine mechanisms. Additionally, it obstructs CCL2-mediated reprogramming of TAMs via paracrine signaling [95] Additionally, microRNAs exert substantial regulatory effects on chemokines. miR-505 targets and modulates STAT3 phosphorylation, subsequently upregulating CCL2 expression in tumor cells [96]. Moreover, circRNA circ-0000069 has been found to target CCL25, sustaining its expression and thereby influencing tumor progression [97].

8. Conclusion

Currently, there are no precedents of chemokines being used directly as drugs for the treatment of breast cancer in clinical practice. However, research has found that CXCL12 is a chemokine that attracts Treg and MDSC. It exerts its effects through NF-κB and ProstaglandinE2 (PGE2)-dependent induction. These two mechanisms suggest that the combination of paclitaxel and CXCL12 inhibitors could enhance the clinical efficacy of neoadjuvant chemotherapy for breast cancer [98]. Similarly, CCR5 plays an important role in the chemotherapy and drug resistance of breast cancer, as it achieves resistance to chemotherapy and radiotherapy by inducing the gene expression that controls DNA damage and repair [99]. Furthermore, research indicates that the expression of the CCL12 gene significantly influences pain outcomes following surgical excision of breast cancer [100]. Not only that, clinical investigators have also discovered a CXCR4 antagonist that blocks CXCL12-mediated endothelial cell recruitment and blocks tumor angiogenesis by inhibiting AKT and ERK pathways [101].

At present, there is no detailed explanation or specific study on the role of chemokines in different subtypes of different breast cancer molecular subtypes, and the role of most chemokines on breast cancer is based on the role of triple negative breast cancer, and our next goal is to refine the specific role of chemokines in cavity and HER2 breast cancer.

In conclusion, while significant progress has been made in understanding the complex interactions within the tumor microenvironment (TME), several critical issues remain unresolved. One of the most pressing challenges is the role of chemokine crosstalk, where multiple chemokine networks interact to influence tumor progression and immune response. The dynamic nature of these interactions complicates the development of targeted therapies, as the influence of chemokines can vary depending on the tumor type, stage and immune cell composition within the TME.

Another key unresolved issue is the inherent heterogeneity of the TME, which presents significant obstacles in developing universal treatment strategies. The TME is composed of a diverse array of cellular populations, including immune cells, fibroblasts, endothelial cells and extracellular matrix components, each of which may exhibit distinct functional states. Understanding the spatial and temporal variations within these cell populations, as well as their interplay, is essential for deciphering the complexity of cancer progression and therapy resistance.

Future Research Directions:

To address these challenges, future research should focus on the following actionable directions:

1. Chemokine Interactions and Crosstalk:

Investigating the molecular mechanisms underlying chemokine signaling and its cross-regulation between different immune and stromal cells within the TME.

Utilizing advanced multi-omics approaches to map the chemokine landscape in various tumor types and stages, enabling the identification of novel therapeutic targets.

2. Tumor Microenvironment Heterogeneity:

Developing and implementing high-resolution imaging techniques to explore the spatial distribution of different cell populations within the TME.

Employing single-cell RNA sequencing and spatial transcriptomics to unravel the cellular diversity and communication networks in tumors, focusing on their dynamic changes during treatment.

Creating more sophisticated in vitro and in vivo models that better replicate the heterogeneity and complexity of the TME to evaluate therapeutic strategies.

3. Targeting Chemokines and TME Crosstalk in Therapy:

Designing therapies that can selectively modulate chemokine pathways or alter TME components to either enhance immune responses or reduce tumor progression.

Investigating combination therapies that target both the TME and tumor cells, aiming to overcome resistance mechanisms by disrupting the functional interactions within the TME.

By addressing these unresolved issues and following the proposed research directions, we can enhance our understanding of the TME’s role in cancer progression and pave the way for more effective and personalized treatment strategies.

Availability of data and materials

This is a review article, and all data sources are cited within the text.

Author contributions

SFY, JLL—made significant contributions to the work, including conceptualization, study design, execution, data acquisition, analysis and interpretation. XL—participated in drafting, revising, or critically reviewing the article, approved the final version for publication, agreed on the journal for submission, and accepted responsibility for all aspects of the work.

Ethics approval and consent to participate

This article is a review and does not involve any experiments requiring ethical approval. All authors participated in the writing and consented to the publication of this paper. This article does not involve any published patient data.

Acknowledgment

I would like to express my sincere gratitude to Yang Shaofeng for providing funding support for this article. I also appreciate all the authors for their contributions and revisions, and I am grateful to the editor for reviewing the article and providing valuable feedback.

Funding

This paper was supported by the Natural Science Foundation of Inner Mongolia Autonomous Region (Grant No. 2022MS08010) and the Graduate Student Excellence Program (YKDD2023ZY001).

Conflict of interest

The authors declare no conflict of interest.

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