Several factors, including chemokines, cytokines, and complements produced by both tumor and normal cells, induce the recruitment of MDSCs into tumor tissue (48). Among these, lung fibroblasts secrete chemokine (C-X-C motif) ligand (CXCL)1, which promotes an immunosuppressive lung microenvironment by attracting granulocytic MDSCs and facilitating the formation of BC metastatic niches in the anterior lung (49).

BC exosomes carry elevated levels of miR-200b-3p, which are taken up by alveolar epithelial type II cells, directly impacting phosphatase and tensin homolog (PTEN). PTEN suppression activates the AKT/NF-κB-p65 pathway, increasing chemokine (C-C motif) ligand 2 (CCL2) expression and attracting MDSCs, ultimately promoting lung metastasis in BC (50). Endoplasmic reticulum oxireductin 1a, a disulfide oxidase located in the endoplasmic reticulum and closely associated with tumors, participates in the oxidative folding process, generating and attracting granulocytic MDSCs, and contributes to G-CSF, CXCL1 and CXCL2 production (51). TGF-β1 upregulates miR-494 levels in MDSCs, enhancing MDSC movement via CXCR4(52). The transcription factor, ΔNp63, directly regulates CXCL2 and CCL22, facilitating MDSC recruitment in TNBC (53).

Liver cells contribute to MDSC recruitment at specific sites by producing S100A8, facilitating BC metastasis (54). Chen et al (55) found that VEGF-C produced by breast cancer cells was responsible for increasing the levels of chemokines produced by lymphatic endothelial cells (LECs). This, in turn, helped recruit MDSCs to the TME and lymph nodes (LNs) through the CXCR2 pathway (55). Evidence suggests that in the presence of 4T1 cells (breast cancer cell line derived from the mammary gland tissue of a mouse BALB/c strain), interstitial fluid migration alongside LECs aids MDSC dissemination. Moreover, reduced levels of vascular VEGFR3 decrease the flow response in MDSCs and 4T1 cells (56). The acetylation of the SMAD3 protein, dependent on the epigenetic regulator KAT6A, contributes to MDSC recruitment and TNBC metastasis through epigenetic regulation (57).

The activation of the complement system, particularly through C5a signaling, plays a pivotal role in recruiting MDSCs into the TME and suppressing CD8⁺ T cell-mediated tumor elimination. Consequently, lung angiogenesis is fostered in tumor-bearing mice, facilitating BC metastasis to this organ (58). Cheng et al (59) demonstrated that periodontal inflammation (PI) activation enhances the expression of chemokines such as CCL5, CXCL12, CCL2 and CCL5, which recruit MDSCs, thereby promoting the establishment of premetastatic niches at sites of inflammation. MDSCs exhibit diverse differentiation pathways regulated by various transcription factors, as depicted in Fig. 1. They can differentiate into tumor-associated macrophages (TAMs) and dendritic cells, which further stimulate the production of inflammatory DCs (60).

During BC progression, MDSCs transition into TAMs. Under environmental pressures, such as hypoxia, M-MDSCs differentiate into TAMs upon migration to specific tissues. TAMs, in turn, can adopt either the M1 phenotype, characterized by pro-inflammatory and antitumor properties, or the M2 phenotype, which exhibits protumor functions, in response to stimuli such as lipopolysaccharide (LPS), TNF-α and IFN-γ (61).

Macrophages and MDSCs are ubiquitous in the majority of solid tumors, driving immune suppression and inflammation (61). Their interaction increases IL-10 production by MDSCs and decreases IL-12 production by macrophages, polarizing the immune system toward a type 2 protumor environment (62). IL-33 is known for its stimulatory effects on myeloid and lymphoid cells, promoting the production of type 2 cytokines. The activation of ST2 in type 2 innate lymphoid cells (ILC2) triggers the release of type 2 cytokines IL-33 and IL-13(63). ILC2 are tissue-resident lymphocytes with various functional roles in mucosal immunity. In tumor immunology, ILC2 is crucial in DC recruitment via CCL5 production and activation through IL-9 and IL-13 secretion (64). IL-33 further stimulates ST2⁺ regulatory T-cells (Tregs) and amphiregulin (AREG) expression, enhancing immune regulatory functions and tissue repair (65). The activation of ILC2 through IL-33 supports type 2 immune responses and M2 reparative macrophages. ST2 is also expressed in myeloid-derived antigen-presenting cells, such as macrophages and CD11b⁺ CD11c⁺ DCs (66). Moreover, IL-33 triggers IL-2 release and fosters Treg cell expansion. The type, density and spatial distribution of these IL-33-modulated immune cells within tumors profoundly influence tumor behavior (67). Thus, the cytokine IL-33 stimulates the upregulation of IL-13 while concurrently suppressing IL-12 levels. This immune profile underlies the negative impact of M2 macrophages and Th2 cell polarization within the TME on antitumor immunity (34).

TAMs are the most abundant immune cells involved in regulating breast cancer progression. The TME contains many immunosuppressive cells (68). Macrophages exhibit heterogeneity, with at least two functionally distinct subtypes responding to different stimuli: classically activated M1 macrophages and alternatively activated M2 macrophages (69). M1 macrophages eliminate tumors directly by recognizing and phagocytizing cancer cells and indirectly by producing pro-inflammatory cytokines, such as IFN-γ and IL-12. Conversely, in the context of tumor development, M2 macrophages are regarded as ‘tumor promoters’. They facilitate cancer progression, promote tumor cell metastasis and angiogenesis, regulate energy metabolism and aid in immune system evasion (70). During tumor progression, M2 macrophages become more prevalent, eventually dominating the TAM population in the TME. The underlying mechanism suggests that TAMs promote and sustain cancer stem cells, thereby supporting tumor growth and self-renewal. Various cytokines and signaling pathways within the TME influence the polarization of macrophages into M1 or M2 types. When IL-4 binds to its receptor, it can promote the phosphorylation of STAT6, leading to the polarization of M2-like macrophages through the JAK/STAT6 signaling pathway (68,71). Phosphorylated STAT6 can bind to Krüppel-like factor 4 (KLF4) and peroxisome proliferator-activated receptor γ, further promoting this polarization. Furthermore, various signals, including TGF-β, IL-10, bone morphogenetic protein-7 and IL-4 itself, induce M2 polarization through the PI3K/Akt signaling pathway. The complex formed by CCAAT/enhancer binding protein α and KLF6 is also associated with the switch from the M1 to the M2 phenotype (71,72). The progression of BC can also be observed through the promotion of monocytic MDSC differentiation into immunosuppressive M2-polarized macrophages, facilitated by both sphingosine synthase 2 and exosomes secreted by mesenchymal stem cells (61,73). Doxorubicin (DOX)-resistant tumor cells release PGE2, activating the EP2-EP4/cAMP/PKA signaling cascade in MDSCs, fostering proliferation and an M2 polarized phenotype shift. This polarization is mediated through miR-10a induction (27). Studies have shown that natural killer (NK) T-cells (NKT cells) help transform CD11b⁺ HLA-DR MDSCs into CD11b low HLA-DR DCs (74).

Fig. 2 shows how MDSCs significantly impede the activity of tumor-fighting T- and B-cells within the TME, particularly cytotoxic T-lymphocytes (CTLs) and pro-inflammatory cells, such as NK cells. Additionally, MDSCs can promote cancer progression by inducing the generation of Tregs and T-helper 17 (Th17) cells, thereby altering the local environment to promote tumor growth and enable immune evasion (75).

The primary immunosuppressive mechanism in the BC microenvironment involves the inhibition of T-cell function, which is the main trigger process involving the depletion of vital nutrients (Fig. 2A) (76). MDSCs exert inhibitory effects by activating indoleamine 2,3-dioxygenase (IDO), reducing local tryptophan availability, and generating cytotoxic metabolites, such as kynurenine in the TME and lymphatic drainage regions. This leads to an increase in Tregs, the inhibition of immune responses against antigens and the suppression of tumor-specific CTLs (77). The activation of STAT3-dependent NF-κB by IL-6 is responsible for maintaining IDO overexpression (30,77). Additionally, MDSCs enhance the suppressive action of IL-33 on T-cells by depleting L-arginine via arginase 1 (ARG1) (33,75). Furthermore, MDSCs consume cysteine, essential for T-cell activation and optimal function, leading to its depletion and failure to replenish in their environment (78). The generation of oxidative stress is a key factor in the second mechanism (Fig. 2B).

By producing reactive oxygen species, reactive nitrogen species and nitric oxide (NO), MDSCs suppress T-cells in the TME. MDSCs induce immune tolerance by T-cell receptor and CD8⁺ surface modifications and generate the free radical peroxynitrite (79). According to Stiff et al (80), MDSC-generated NO also disrupts Fc receptor-mediated NK cell activity, reducing monoclonal antibody efficacy and impeding the immune response against tumors. The third mechanism occurs by preventing lymphocyte migration (Fig. 2C). MDSCs reduce the immune response in peripheral lymphoid organs and accumulate in sentinel LNs, where they impede CD3/CD28-induced T-cell proliferation through contact-dependent mechanisms. This process supports tumor progression and metastasis (80,81). Hanson et al (82) linked decreased L-selectin expression on CD4⁺ and CD8⁺ T-cells with a disintegrin and metalloproteinase domain 17 generation on the plasma membrane. Consequently, MDSCs in BC hinder immature T-cell activation and migration into LNs and their subsequent transport to tumors, ultimately compromising the immune system's capacity to combat tumors (82).

The fourth aspect pertains to the expansion and activation of Tregs, facilitated by MDSCs via promoting their proliferation and differentiation of naïve CD4⁺ T cells (Fig. 2D). Although this pathway mechanism is not yet fully understood, it is known that Tregs can infiltrate tumors and play a crucial role in the antitumor immunosuppressive response. IL-34 triggers the conversion of bone marrow stem cells into monocytic MDSCs, indirectly suppressing the immune response by fostering Treg attraction via CCL22 secretion in the TME, thus contributing to chemotherapy resistance (35). Additionally, BC-induced MDSCs can stimulate effector T-cells to transition into Tregs through the IDO mechanism (77). MDSCs suppress T-cell activation, and once activated, T-cells trigger MDSC apoptosis via the Fas-FasL pathway (83).

MDSCs in BC employ contact-dependent mechanisms and indirect means, releasing NO, ARG and IL-1 to suppress the response of B-cells against tumors (84). Additionally, MDSCs can transform ordinary B-cells into specialized immunomodulatory B-cell (Breg) phenotypes, which efficiently suppress T-cell responses (85). Furthermore, various mediators in the TME, including LPS, can induce programmed cell death protein 1 (PD-1) expression in MDSCs in BC (86). By activating the PI3K/PKB/NF-κB signaling pathway in B-cells, MDSCs can enhance immune evasion mediated by PD-1/PD-L1 Bregs through the PD-1 pathway (87,88).

BC cells cultured under hypoxic conditions secrete various cytokines, including monocyte chemotactic protein-1, which triggers MDSC recruitment and suppresses the cytotoxic activity of NK cells. These mechanisms collectively contribute to cancer metastasis facilitation (89). NKT cells can restore suppressed T-cell function by converting CD11b⁺ HLA-DR MDSCs into CD11b low HLA-DR DCs through an NKG2D-dependent signaling mechanism (74). The function of MDSCs is further influenced by C5aR signaling, regulating CD4⁺ T-cell polarization towards the Th2 phenotype in the lungs of tumor-bearing mouse (58). The administration of DOX increases miR-126 exosomes derived from MDSCs, thereby suppressing T-cell functionality, inhibiting Th1 cell activation, and initiating Th2 cell responses in mouse lungs (90).

MDSC levels are associated with the progression of BC, typically showing higher levels in more advanced cancer stages (22). Additionally, surgical stress induced by the excised primary tumor environment can trigger the recruitment of MDSCs to lung and tumor tissues, underscoring the importance of monitoring MDSC levels (91). Data indicate variations in MDSC levels among patients undergoing antitumor treatment, potentially reflecting individual responses to therapy. In neoadjuvant therapy, circulating granulocytic MDSCs may initially increase, decrease with DOX and cyclophosphamide administration, and return close to baseline levels during paclitaxel treatment. Conversely, in metastatic or recurrent BC, monocytic MDSCs undergo significant expansion in the peripheral circulation, being associated with increased degrees of metastases to LNs and other organs (92). Therefore, tracking M-MDSC levels in patients with BC may be a valuable biomarker for monitoring cancer progression and treatment response.

MDSCs play a pivotal role in BC progression and are intricately linked to tumor immune evasion. Consequently, MDSCs are a promising target for tumor immunotherapy, primarily aimed at enhancing host immunity. Currently, therapeutic strategies targeting MDSCs encompass four main approaches, as illustrated in Fig. 3: MDSC depletion, the blockade of MDSC recruitment, the suppression of MDSC immunosuppressive function and the induction of MDSC differentiation into a non-suppressive immune state (93-95).

While no specific selective inhibitors of MDSCs have been identified to date, at least to the best of our knowledge, several existing drugs exert indirect effects on MDSCs. For instance, DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors modulate systemic and intratumoral MDSCs, enhancing the long-term response to immunotherapy (96). Other drugs with the potential to suppress or deplete MDSCs and consequently enhance immunotherapy efficacy include gemcitabine (97), DOX (98) and 5-fluorouracil (99). Additionally, combined therapeutic strategies are under investigation, such as the combination of Romidepsin (an HDAC inhibitor) with cisplatin and nivolumab in TNBC (NCT02393794) (100) and IPI-549 (an inhibitor of PI3Kδ and PI3Kγ isoforms that decreases MDSCs and enhances anti-PD-1 efficacy) with nivolumab in solid tumors (101).

Curcumin is known for its antitumor properties, primarily attributed to its inhibition of IL-6. However, research has revealed that its mechanism also entails the inhibition of MDSCs in both blood and tissues, thus impeding tumor growth (102). Numerous preclinical and clinical studies are also dedicated to exploring strategies for promoting MDSC maturation (103-105). Sulforaphane, an inhibitor of the inflammatory cytokine MIF, disrupts its protumor functions, including the facilitation of MDSC differentiation in the TME. In vitro research has shown that MIF inhibitors, such as sulforaphane inhibit the accumulation of MDSCs in the TME, blocking their differentiation and restoring antitumor immunological activity (36). Silibinin modulates CCR2 expression in MDSCs, resulting in decreased MDSC accumulation in blood and tumor tissue (106). NG-monomethyl-L-arginine acetate, an inducible NO synthase inhibitor, blocks MDSC differentiation into osteoclasts, potentially preventing MDSC-mediated BC bone metastasis and associated bone degradation (107). Activated T-cells (ATCs) combined with bispecific anti-CD3 x anti-Her2/neu antibodies (aATCs) effectively modulate MDSCs via INF and IL-2, suppressing their activity and inhibiting tumor growth (108). According to Thakur et al (109), aATCs suppress the actions and functions of MDSCs (via IFN and IL-2) and effectively inhibit tumor growth and Treg differentiation.

Therapeutic combinations, such as adoptive cell therapy involving sensitized immune and tumor cells reprogrammed with CD25⁺ NKT, NK and memory T-cells, have achieved the immunosuppression of MDSCs (110). In other strategies tested in preclinical models, a vaccine composed of Listeria monocytogenes has been investigated. When MDSCs are infected with a highly attenuated bacterium, Listeria monocytogenes (Listeria^at), their immunosuppressive function is altered. Moreover, Listeriaat-infected MDSCs, which primarily deliver Listeriaat to the microenvironment of metastases and primary tumors, spread from MDSCs to tumor cells. Consequently, Listeriaat immunotherapy significantly reduces the population of MDSCs and can convert MDSCs into an immunostimulatory phenotype that produces IL-12, while concurrently reducing metastasis and tumor growth (111).