Chemotherapy is the standard treatment for TNBC, with commonly used agents including anti-microtubule agents such as taxanes (paclitaxel), anthracyclines (doxorubicin), alkylating agents (cyclophosphamide) and fluorouracil (11). Although chemotherapy can be effective, it is associated with toxicity and variable patient outcomes (8). Another limitation is intrinsic or acquired chemotherapy resistance, which is common in TNBC and is the primary obstacle to effective treatment (12). It is therefore prudent to explore additional therapeutic options. Numerous immunotherapy and targeted therapy strategies, including immune checkpoint inhibitors, PARP inhibitors, and antibody-drug conjugates, are under investigation for their potential effectiveness against TNBC (13). In addition, studying the interaction of TNBC tumors with the tumor microenvironment (TME) may help increase immunotherapy effectiveness (14). Nevertheless, developing new therapies for TNBC remains challenging, with a small number of approved targeted therapies available, such as poly-ADP-ribose polymerase and immune checkpoint inhibitors (13). As such, treatment mostly depends on chemotherapy, surgery and radiation, which typically cause serious side effects and have decreased effectiveness (15,16). These challenges underscore the urgent need for novel therapeutic strategies that may overcome resistance and improve outcomes for patients with TNBC.

Chemokines are small proteins that regulate guided cellular movement, with ~50 members identified in mammals (17). The TME is the primary site of interaction between tumor cells and the host immune system (18). Through interactions between chemokines and chemokine receptors, numerous immune cell subsets are recruited into the TME, with differential effects on tumor progression and treatment results (18). The CXC chemokines are a distinct family of cytokines that contain four highly conserved cysteine amino acid residues, with the first two cysteine residues separated by one non-conserved amino acid residue (19). These chemokines are key regulators of the progression and spread of BC due to their ability to control leukocyte infiltration and TME interactions (20). The present review primarily examines CXCL1 chemokine, which is also known as growth-regulated oncogene-α and melanoma growth stimulatory activity-α, due to its role as a key mediator of TNBC progression (21). CXCL1 belongs to the ELR⁺ chemokine group due to the presence of the tripeptide motif (Glu-Leu-Arg) at the NH2 terminus (22).

A total of three receptors for CXCL1 have been identified: CXCR1 and 2 and atypical chemokine receptor 1 (ACKR1) (23). CXCL1 binds CXCR2 with high affinity and CXCR1 with low affinity (24). ACKR1 interacts with CXCL1 with binding characteristics comparable with those observed between CXCL1 and CXCR2 (23). In BC, particularly TNBC, ACKR1 expression is associated with regulation of angiogenesis, metastatic behavior and immune cell infiltration (25). The role of ACKR1 in CXCL1 function, however, is not fully understood and requires further experimental validation (26).

Numerous reviews have addressed the role of CXCL1 in BC and concluded that CXCL1 promotes cancer cell proliferation and migration (26–28). Beyond its direct tumor effects, CXCL1 influences the TME by recruiting immune cells such as myeloid-derived suppressor cells (MDSCs) and neutrophils, and inducing angiogenesis via endothelial CXCR2 (23,26,27). Notably, Korbecki et al (26) summarized the involvement of CXCL1 in BC progression, highlighting its role in tumor progression, metastasis and immune cell recruitment, as well as therapeutic strategies targeting CXCL1 and its receptors in cancer (27).

CXCL1 is typically overexpressed in aggressive BC subtypes, including TNBC (26,27). Recent studies have highlighted CXCL1 as a potential therapeutic target in TNBC (29–31). Despite increasing evidence of its involvement in tumor progression, immune modulation and the TME (21,22,26,27), to the best of our knowledge, no comprehensive review has focused exclusively on the role of CXCL1 in TNBC.

The present review summarizes the value of targeting CXCL1 in TNBC, a subtype marked by poor prognosis and the absence of effective targeted therapy, the expression patterns and cellular sources of CXCL1 in TNBC, along with key signaling pathways associated with its activity, as well as how CXCL1 shapes tumor behavior and the TME, including its interactions with immune cells and involvement in extracellular vesicle (EV)-mediated communication. Finally, it explores therapeutic strategies aimed at modulating the CXCL1 axis and outlines challenges that continue to hinder clinical translation.

Elevated CXCL1 expression in BC tissue is associated with advanced tumor stage and poor prognosis (32). CXCL1 expression may differ between BC subtypes. For example, CXCL1 is highly expressed in ER-negative BC compared with ER-positive subtypes (33,34). Although CXCL1 is expressed in 3.67% of BC cases in the Pan-Cancer dataset, with ~2 million cases diagnosed annually worldwide, this corresponds to ~73,000 CXCL1-positive cases each year (35). As 69% of patients with CXCL1-positive BC are diagnosed with TNBC, CXCL1 expression might serve a role in the malignant phenotype of this disease (35).

Expression of CXCL1 is elevated in TNBC compared with other subtypes in human BC tissues (33,36–38). Elevated CXCL1 expression is associated with BL subtypes of BC (39). The BL subtype is common in TNBC, accounting for 70–80% of cases (40). CXCL1 expression is also elevated in M TNBC (38). Because these subtypes are characterized by distinct molecular characteristics, the functional consequences of CXCL1 upregulation may differ according to subtype context. For example, given that CXCL1 has been reported to promote tumor cell proliferation in TNBC (36), its elevated expression in BL tumors may further contribute to the highly proliferative phenotype characteristic of this subtype (9). Within the BL subtype, BL1 and BL2 differ in their molecular programs, with BL1 exhibiting the strongest enrichment in proliferation-associated pathways (9). However, despite the higher proliferative signature of BL1, the relative contribution and functional impact of CXCL1 in BL1 vs. BL2 remain insufficiently defined, and additional studies are needed to clarify these distinctions.

In M TNBC which is characterized by upregulation of signaling pathways that promote epithelial-mesenchymal transition (EMT) and cell motility (9), CXCL1 may contribute to these processes through its ability to modulate EMT regulators in TNBC cells (36). The IM subtype is highly enriched in immune cell signaling (9). Given its interaction with immune cells in TNBC (41–43), it is important to determine whether CXCL1 interacts differently with immune cells in the IM compared with other subtypes. However, direct experimental evidence linking CXCL1 to specific downstream signaling pathways in individual TNBC subtypes is limited (44). Most studies have examined general TNBC contexts without stratification into BL1, BL2, M or IM subtypes (27,44,45). Accordingly, the proposed subtype-specific roles are largely hypothetical and require validation in subtype stratified cell lines, patient-derived models or single-cell transcriptomic analyses. A summary of CXCL1 expression patterns and proposed functional consequences across TNBC molecular subtypes is provided in Table I.

Beyond molecular subtypes, Bièche et al (46) showed that the TNBC cell line MDA-MB-231 produces the highest levels of CXCL1 among BC cell lines. Furthermore, this increased CXCL1 expression is induced by various cancer therapies (27). For example, CXCL1 expression in TNBC is induced by chemotherapeutic agents, such as doxorubicin (47) and paclitaxel (30) in MDA-MB-231 cells. High CXCL1 expression does not occur in all TNBC cell lines, with BT-20 cells being an example (26).

In TNBC, CXCL1 is produced by multiple cell types, including BC and tumor-associated immune cells in the TME (35). To explore the significance of CXCL1 in TNBC, it is important to identify which cells in the TME are responsible for its production. Tumor-associated macrophages (TAMs), a primary immune cell population within tumors, are broadly classified into pro-inflammatory, anti-tumor M1 macrophages and immunosuppressive, tumor-promoting M2 macrophages, with the latter supporting tumor growth, metastasis and angiogenesis (48). CXCL1 is secreted in high amounts by TAMs (39,48). More specifically, CXCL1 is secreted by M2-polarized TAMs in the TME (49,50).

Cancer associated fibroblasts (CAFs) are another source of CXCL1 in TNBC (37). CAFs arise primarily from tissue-resident (quiescent) fibroblasts and include all fibroblasts present in the tumor that interact with cancer cells (51). CAFs produce extracellular matrix and reprogram immune surveillance in the TME (44). CAFs treated with neoadjuvant chemotherapy release ELR⁺ chemokines, which include CXCL1 (52).

In addition, BC stem cells (BCSCs) are a small but key subset of heterogenous BC cells that exhibit potent proliferative and self-renewal abilities (53). TNBC exhibits marked enrichment of BCSCs (54). It has been hypothesized that BCSCs could potentially serve as a notable source of CXCL1 in TNBC (35). Overall, CXCL1 is abundantly expressed in TNBC and originates from multiple cell types.

CXCL1 expression is regulated by intracellular signaling pathways and external stimuli within the TME. Chemokine expression is regulated by NF-κB signaling (55–57). CXCL1 is a transcriptional target of NF-κB, which, upon activation, promotes CXCL1 expression (23,58,59). IκB kinase-mediated phosphorylation of the NF-κB inhibitor (IκB) marks it for ubiquitination and leads to its degradation, enabling NF-κB to enter the nucleus and activate transcription of tumor-promoting chemokines such as CXCL1 (57) (Fig. 1). Elevated NF-κB activity is associated with ER-negative BC, especially BL subtypes (60). TNBC, in particular, is characterized by high levels of constitutively active NF-κB signaling (61). Additionally, the increase of CXCL1 via NF-κB in BC is associated with the use of chemotherapeutics (27,47). This is observed in TNBC, where doxorubicin activates NF-κB in MDA-MB-231 cells resulting in the expression of several genes, including CXCL1 (47).

The NF-κB pathway is regulated by multiple modulators that might affect CXCL1 expression (Fig. 1). For example, IL-17 activates NF-κB signaling (62,63). IL-17 also induces CXCL1 expression in TNBC cells (64,65). Furthermore, chemotherapy increases tumor necrosis factor (TNF)-α expression in the TME, which increases CXCL1 levels in BC cells (7). Consistently, the NF-κB pathway is induced by TNF-α in TNBC cells, leading to increased expression of CXCL1 (41,59). A total of ~84% of TNBC cases exhibit upregulated transmembrane TNF-α (tmTNF-α) (66). This may be associated with increased CXCL1 expression, potentially through NF-κB dependent mechanisms (57–59). This suggests tmTNF-α as a potential tumor biomarker, with further research required. Finally, CXCL1 expression mediated by NF-κB may be induced by the transcription factor forkhead box C1 in TNBC cells (58).

TNBC cells exhibit increased activation of Akt. These cells express elevated levels of epidermal growth factor receptor (EGFR) and release more transforming growth factor (TGF)-α, the primary ligand for EGFR, compared with other BC subtypes (38). It is hypothesized that TGF-α- and EGFR-mediated activation of Akt may contribute to the increased expression of proinflammatory chemokines in TNBC (38).

CXCL1 interacts with immune cells by attracting myeloid cells (41). For example, a recent study in 4T1 TNBC cells revealed that CXCL1 promotes the mobilization of splenic MDSCs to the lung, a key step in pre-metastatic niche (PMN) formation (50). The aforementioned study showed that chronic psychological stress activates TAM/CXCL1 signaling in the TME via the glucocorticoid receptor (GR) pathway, with elevated cortisol levels enhancing GR binding to the CXCL1 promoter in TAMs (50). This upregulation of CXCL1 promotes the proliferation, movement and immunosuppressive functions of MDSCs via CXCR2, facilitating their recruitment and PMN formation (50). Similarly, another study has shown that CXCL1 may indirectly mediate the interaction between macrophages and BC cells in the PMN, which contributes to BC progression (42). Moreover, CXCL1 promotes the recruitment of hematopoietic stem and progenitor cells (HSPCs) from the bone marrow and their differentiation into MDSCs in the TME (77).

In addition to MDSCs, CXCL1 also plays a crucial role in attracting tumor-associated neutrophils (TANs) to the TME (33,43,64). TANs are highly present in the TNBC tumor niche. Tumor-associated factors, including cytokines, are involved in promoting their production in the bone marrow and recruitment to the tumor site (78). TNBC cell lines secrete notably higher levels of neutrophil-activating factors, including CXCL1, compared with ER-positive cells, resulting in strong neutrophil migration (33). This recruitment may depend on the combined effects of Growth-regulated oncogene (GRO) chemokines, such as CXCL1, and TGF-β found in the tumor conditioned media harvested from TNBC cells (33). TGF-β also induces an N2 protumor phenotype of TANs in the TME (79). TAN recruitment is typically mediated via CXCR2 in TNBC (23,80,81). However, neutrophil-recruiting activity of tumor conditioned media remains intact after blocking CXCR2, indicating that CXCL1/CXCR1 signaling may also play a role in neutrophil recruitment in TNBC cell lines (33). Additionally, CXCL1/TAMs are primarily implicated in immune evasion and therapy resistance in TNBC (48,49).

TAMs are a key immune population in TNBC. TNBC tissue shows notable infiltration of M2 macrophages (49). M2-TAMs may promote autophagy and contribute to BC cell resistance to chemotherapy with the involvement of CXCL1 (48). CXCL1 may induce autophagy by regulating the insulin-like growth factor 1/insulin-like growth factor 1 Receptor pathway (48). This promotes chemoresistance to paclitaxel in MDA-MB-231 cells (48).

PD-L1, the primary ligand of the coinhibitory receptor PD-1, regulates immune tolerance by preventing overactive immune responses (82). Cancer cells exploit this process and typically express PD-L1 to evade immune attack, a strategy associated with poor patient outcomes (82). A recent study showed that CXCL1 secreted by M2 macrophages in the TME promotes PD-L1 upregulation in TNBC via activation of the CXCR2-mediated phosphoinositide 3-kinase (PI3K)/AKT/NF-κB signaling pathway, which reveals the immunosuppressive role of M2 macrophages and CXCL1 (49) (Fig. 2).

Additionally, tumor cells release EVs, which have the potential to act as mediators of intercellular communication in the TME, impacting cancer progression (83). This has been described in TNBC (30,84). Chemotherapeutic agents such as paclitaxel induce the release of CXCL1-enriched EVs from dying TNBC cells (30). These CXCL1-containing EVs (CXCL1 EVs) induce macrophage M2 polarization by upregulating PD-L1 expression (30). EVs are phagocytosed by macrophages and the CXCL1 cargo is released into the cytoplasm (30). It is likely that CXCR2 does not serve a role in this process (30). Mechanistically, CXCL1 EVs promote embryonic ectoderm development (EED) protein expression and its nuclear translocation. EED then binds to the PD-L1 promoter, enhancing PD-L1 transcription (30). Through this TAM/PD-L1 signaling pathway, CXCL1 EVs drive TNBC tumor growth and lung metastasis (30). This process also contributes to chemotherapy resistance in TNBC (84). This suggests that chemotherapy may paradoxically drive pathways that promote chemoresistance in TNBC, emphasizing the need for alternative treatment options. Overall, CXCL1 links macrophage polarization, PD-L1 expression and EV-mediated communication into a unified axis of immune evasion and therapy resistance in TNBC (Fig. 2).

The CXCL1/CXCR2 pathway plays a key role in TNBC, making it a relevant focus for therapeutic development. CXCR2 expression is upregulated by chemotherapeutic agents such as doxorubicin in TNBC cells (85). Elevated CXCR2 expression is associated with poorer prognosis in patients with TNBC, as it is implicated in chemotherapy resistance (85,86). Combining CXCR2 antagonists with traditional chemotherapy or immune checkpoint inhibitors suggests CXCR2 inhibition is a viable approach to counteract chemoresistance and enhance immunotherapy in TNBC (85). Several antagonists targeting CXCR2 such as reparixin, SB225002 and AZD5069 have been developed (27). Reparixin, a non-competitive allosteric inhibitor, does not show an advantage when combined with paclitaxel in patients with advanced TNBC, compared with paclitaxel treatment alone (27,87). Alternatively, SB225002 increases apoptosis in TNBC cells (45). Although SB225002 has shown effectiveness against multiple types of cancer, including TNBC, this compound has not yet been tested in clinical trials (27). For AZD5069, an in vitro study using MDA-MB-231 mammospheres has shown that this small-molecule CXCR2 antagonist enhances the effectiveness of the anti-PD-L1 immune checkpoint inhibitor atezolizumab and decreases doxorubicin chemoresistance in 3D TNBC cultures (85). This effect may be mediated through disruption of the aforementioned TAM/CXCL1/CXCR2/PD-L1 signaling pathway (49). In summary, SB225002 and AZD5069 show promise in preclinical models of TNBC but it is crucial to investigate their therapeutic potential in clinical trials.

There is evidence in the literature that suggests contrasting effects of CXCR2 and its inhibition (37,88,89). A study on metastatic sub-clones of 4T1 breast carcinoma cells has shown that blocking CXCR2 activity leads to an increase in CXCL1 secretion (89). This may be a result of CXCR2 serving as an auto-receptor for its ligands (89). As aforementioned, some pathways mediated by CXCL1 in TNBC may be independent of CXCR2 activation (30,33).

Moreover, higher levels of CXCR2 may be associated with a better prognosis in patients with BC (37,88). Several factors may help explain the inconsistent findings regarding CXCR2 prognosis in BC. One possibility is that differences in cell sources of CXCR2 within the TME influence outcome associations. For example, stromal immune cells, particularly TANs, express high levels of CXCR2 (88), and certain antibodies used in earlier studies may preferentially stain stromal rather than malignant cells (37,88).

TNBC expresses greater levels of CXCR2 compared with luminal or HER2-positive BC. This CXCR2 is mostly expressed by neutrophils in breast tumors (88). TANs facilitate T cell activation in response to chemokines in the TME, which may contribute to their anti-tumor activity (90). Consistently, high CXCR2 expression is associated with increased tumor-infiltrating lymphocytes, a feature typically associated with better prognosis in patients with TNBC (88). This implies that increased CXCR2 expression on infiltrating immune cells may promote improved TNBC outcomes (88).

Although numerous mediators have been implicated in shaping the pro- or anti-tumoral functions of immune cells (91), the mechanisms governing how TNBC cells regulate the expression and secretion of these factors, such as CXCL1 and associated chemokines, and how these mediators interact to influence CXCR2-dependent neutrophil behavior remain incompletely understood. Collectively, the aforementioned findings highlight the need for studies that discriminate between stromal and tumor-intrinsic CXCR2 expression and define how CXCR2-dependent immune infiltration patterns influence clinical outcomes in TNBC. Given the inconsistent evidence on CXCR2 prognosis and inhibition effects, it is important to examine potential CXCL1 inhibitors, as well as the CXCL1/CXCR1 pathway, which may offer a more effective approach in TNBC.

While most literature in TNBC focuses on CXCL1 signaling via CXCR2, the CXCL1-CXCR1 axis may also be biologically and therapeutically relevant in cancer (33,92). CXCR1 is upregulated in breast tumors compared with normal tissue and may serve as a biomarker for malignancy, invasiveness and prognosis (92). Furthermore, CXCR1 blockade selectively depletes CSC populations in MDA-MB-453 TNBC cells, highlighting the role of CXCR1 in CSC maintenance in BC (93).

As aforementioned, the neutrophil-recruiting activity of tumor conditioned media remains intact after blocking CXCR2, indicating that CXCL1/CXCR1 signaling may also play a role in neutrophil recruitment in TNBC cell lines (33). A recent in vivo study revealed that CXCR1/2 dual antagonism impairs neutrophil polarization toward immunosuppressive phenotypes (94). This implies that CXCR2 blockade alone may be insufficient, as CXCR1 may sustain certain immune-suppressive functions when CXCR2 is blocked.

Beyond BC, the CXCL1-CXCR1 axis may be implicated in other malignancies. For example, colorectal cancer is associated with elevated circulating levels of both CXCL1 and CXCR1 (22), suggesting that this ligand-receptor pair may act as a biomarker and potentially drive malignant behavior.

Taken together, the aforementioned findings support the hypothesis that CXCR1 signaling represents a potential escape mechanism, which highlights the possibility that compensatory CXCR1 signaling may undermine the efficacy of CXCR2-directed therapy. Consequently, dual CXCR1/2 inhibition or combination regimens may offer superior therapeutic benefit by reducing the likelihood of compensatory escape in TNBC, although this requires further experimental validation. While dual CXCR1/2 inhibition may provide superior therapeutic benefit by limiting compensatory escape, whether blockade of CXCR1 alone is sufficient to achieve anti-tumor effects in TNBC remains to be determined.

Targeting CXCL1 might be a useful strategy to limit the BCSC subpopulation within the tumor and enhance the effectiveness of immunotherapeutic treatments for aggressive BC (35). One promising therapeutic approach to target CXCL1 involves HL2401, a monoclonal antibody against human CXCL1 (95). Preclinical studies have shown that HL2401 inhibits tumor cell proliferation, migration and angiogenesis in bladder and prostate cancer models, but it has not yet been evaluated in clinical trials (27,95). Although HL2401 has shown promise in certain types of cancer, its potential in TNBC remains unexplored and requires investigation.

Given the importance of CXCL1 in TNBC, several natural compounds have been investigated to inhibit CXCL1 and block its downstream effects. One example is the XIAOPI formula (XPS), which has been the focus of preclinical studies in TNBC (29,31,77). XPS is a traditional Chinese medical preparation composed of 10 medicinal herbs and containing 196 compounds (96). XPS has been approved for the treatment of mammary hyperplasia by the National Medical Products Administration of China, and is prescribed to patients at high risk of developing BC (29). In TNBC, a study on 4T1 cells showed that XPS inhibits the proliferation and metastatic ability of cancer cells in the TME (77). More specifically, XPS inhibits the formation of TAM-induced PMN in mice by suppressing CXCL1-mediated MDSC activation, which might inhibit lung metastasis (77). XPS also suppresses the early-stage rise of HSPCs in BC and their mobilization by CXCL1, exhibiting minimal hematopoietic toxicity (77). Furthermore, XPS inhibits M2 phenotype polarization, CXCL1 expression and suppresses breast tumor growth and BCSC activity in mouse 4T1 ×enografts without detectable side effects (97). These effects may be due to the inhibition of CXCL1 mRNA and protein expression by XPS (77). A recent clinical study showed that XPS decreases CXCL1 serum levels in patients with TNBC following administration for 3 months, suggesting that it could improve clinical outcomes (29).

Through bioactivity-guided fractionation, baohuoside I (BHS) was identified as the principal active compound in XPS responsible for suppressing CXCL1 transcription and producing the effects of XPS (98). BHS demonstrates strong in vivo efficacy, inhibiting BC metastasis in zebrafish (98) and mouse (84) models by targeting the TAM/CXCL1 pathway, while showing no signs of embryotoxicity or teratogenicity in zebrafish embryos (98). Furthermore, a recent study of TNBC cells showed that BHS inhibits CXCL1 cargo in EVs derived from apoptotic tumor cells, which inhibits M2 polarization of TAMs and PD-L1 expression and chemosensitizes BC cells to paclitaxel in vivo by suppressing EV/CXCL1/TAM/PD-L1 signaling (84). Moreover, XPS increases TNBC sensitivity to chemotherapy by blocking CXCL1-induced autophagy (99). Similarly, BHS inhibits the autophagic activity induced by paclitaxel in tumor tissue without inducing toxic side effects (84). Thus, BHS, a naturally abundant compound that can be easily synthesized, combines with paclitaxel to effectively suppress breast tumor growth and lung metastasis, offering a potentially safer and more accessible alternative to costly immune checkpoint inhibitors that may lead to adverse effects (84).

Another natural compound is pentagalloylglucose (PGG), a polyphenol found in multiple medicinal herbs, that exhibits biological therapeutic activity for many diseases, including cancer (100). PGG inhibits TNF-α stimulated CXCL1 mRNA and protein expression and induces apoptosis in TNBC cells (59). The decrease in CXCL1 release may be caused by suppressing the translation of genes involved in NF-қ and MAPK signaling (59). Also, ginsenoside panaxatriol (GPT), one of the primary active components in Panax ginseng herb, has been reported to decrease the expression of inflammatory cytokines including CXCL1, thereby resensitizing TNBC cells to paclitaxel treatment (101).

Small molecule inhibitors have been investigated for their potential to modulate the CXCL1 pathway in TNBC. One of these agents is [(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1), an IκB kinase inhibitor, which has been shown to downregulate inflammatory responses via the inactivation of the NF-κB pathway (102). Similar to the effects observed with XPS and BHS, TPCA-1 enhances TNBC chemosensitivity to paclitaxel, decreases CXCL1 content in EVs derived from apoptotic cells and inhibits tumor growth and lung metastasis in vivo (30). TPCA-1 displays minimal toxicity, indicating its potential as a safe adjuvant to eliminate pro-tumor signals from dying cells (30). Although NF-κB pathways may serve a role in the inhibitory effect of TPCA-1 on CXCL1 expression, the findings on mechanisms of TPCA-1 are scarce (30).

Another example of small molecule inhibitors is differentiation-inducing factor-1 (DIF-1), which is secreted by Dictyostelium discoideum amoeba and known to exhibit anticancer activity (103). It is reported to decrease CXCL1 and CXCR2 expression in 4T1 cells (103). The aforementioned study also proposed that the anticancer effect of DIF-1 may be associated with suppression of communication between BC cells and CAFs mediated by the CXCL/CXCR2 pathway (103).

By contrast with the aforementioned agents that suppress CXCL1 activity, belinostat, a histone deacetylase inhibitor, induces CXCL1 expression, leading to enhanced drug sensitivity and a potentially favorable prognosis in TNBC (71). Belinostat-induced CXCL1 upregulation may cause DNA damage that renders the TME less supportive of tumor cell proliferation, yet treatment-driven selective pressure could trigger adaptive resistance, leaving the role of CXCL1 uncertain (71). These contradictory effects require further investigation.

Given the lack of effective targeted therapy and poor prognosis of TNBC, inhibiting CXCL1 serves as a potentially effective approach that may complement existing treatments. The aforementioned agents modulate CXCL1 in TNBC, affecting tumor progression and highlighting its potential as a therapeutic target. Although multiple CXCL1-targeted strategies have shown promise in preclinical TNBC models (98,102,103), their clinical applicability remains uncertain. Several compounds, such as XPS and BHS, are supported primarily by limited in vitro or small animal studies (84,98,99), with no pharmacokinetic, toxicity or efficacy data in humans. These agents should therefore be interpreted as early exploratory tools rather than clinically mature therapeutics. Collectively, the aforementioned findings indicate that CXCL1 inhibition represents a potential therapeutic strategy for TNBC, with certain agents such as XPS/BHS (29,98) demonstrating greater translational readiness (Table II).

Given the heterogeneity of TNBC, it is possible that only specific patient subsets would benefit from CXCL1-targeted approaches. For example, CXCL1-targeted therapy may be most relevant in TNBC tumors characterized by a strong CXCL1/CXCR2 transcriptional signature. In addition, TNBC subtypes characterized by BL or mesenchymal phenotypes, which tend to show elevated CXCL1 activity, might be more responsive to CXCL1 blockade. However, these considerations remain speculative, as no clinical trials have yet stratified TNBC patients according to CXCL1/CXCR2 status. Overall, these considerations underscore the need for biomarker-driven patient selection and well-designed early-phase trials for determining which subgroups could realistically benefit from CXCL1-targeted therapies.