Breast cancer (BC) is the most prevalent malignancy affecting women globally. Although the majority of BC patients receive timely diagnosis and effectively treatment, there remains a subset of patients with recurrent or metastatic BC. Drug resistance and immune evasion have emerged as pressing challenges in cancer drug therapy. Recent advancements in tumor immunity research, have elucidated that immune escape plays a pivotal role in tumor initiation and progression.
Tumor cells employ diverse strategies to evade immune surveillance include immunoediting to alter immunogenicity [1] and exploitation of tumor microenvironment to evade recognition and elimination by the immune system [2]. A range of anti-tumor immune mechanisms have been discovered including tumor vaccines that enhance antigen recognition by the immune system, adoptive cell therapy which supplements cytotoxic immune cells, and immunotherapy targeting inhibitory checkpoints on T-cells to counter immunosuppression [3].
The use of immune checkpoint inhibitors (ICI) in breast cancer treatment has shown significant progress; however, the gene expression patterns of immune checkpoints vary, and the therapeutic evaluation values of different immune checkpoints in tumors also differ. In this review article, we provide an overview of general aspects related to immune checkpoints and explore recent advancements in strategies to suppress these checkpoints for  treatment of breast cancer. Additionally, we highlighted recent research breakthrough concerning breast cancer-related immune checkpoints.

Immune system serve as crucial defense mechanism against external pathogens. Insufficient immune response may increase the susceptibility to infection and tumor, while excessive immune response can trigger autoimmune diseases [4]. To regulate immune activity, co-inhibitory molecules also known as immune checkpoints control overactivation of effector cells and prevent immune related damage [5]. T cells play vital role in immune system, and involve in recognizing specific antigens,  activating and producing immune response. Activation of immune checkpoints suppresses immune cells, impairing their cytotoxic capbabilities, thus granting tumor survival advantages [6]. Tumor immunotherapy employs immune checkpoint inhibitors to reduce the immunosuppression restoring anti-tumor immunity and facilitating tumor. Currently, FDA has approved four types of immune checkpoint inhibitors: Ipilimumab, effectively inhibits Cytotoxic T Lymphocyte Antigen 4 (CTLA-4); Pembrolizumab and Nivolumab, inhibiting Programmed Death1 (PD-1); and Atezolizumab, which effectively inhibits Programmed Death Ligand 1 (PD-L1) [7], shown in Figure 1.

Gaynor’s research revealed a significance presence of immune checkpoints within breast cancer tissues [8]. Notably, the expression levels of immune checkpoints vary across different BC subtypes. For instance, CTLA-4 and PD-1 exhibit the highest specificity in triple-negative breast cancer (TNBC), while ADORA2A is predominantly expressed in hormone receptor-positive BC. The prognostic value and efficacy evaluation of immune checkpoints in BC vary as well. The expression of B7-H3 mRNA in BC is inversely correlated with prognosis, particularly in luminal patients. Conversely, higher expression of TIGIT in BC indicates a better prognosis. Additionally, expression of B7-H3 is inversely associated with the efficacy of cyclophosphamide [9]. The subsequent section outlines prominent research findings and advancements in the field of BC related immune checkpoints.

Programmed cell death protein 1(PD-1)

PD-1, a class of inhibitory regulatory receptors on the surface of T cells, belongs to the immunoglobulin superfamily type I transmembrane glycoprotein and usually expressed on active cells such as T cells, natural killer cells, B cells, and macrophages [10]. Structurally, PD-1 is a type I transmembrane protein featuring a cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM) [11]. Its inhibitory effects extend to NK cell cytotoxicity and cytokine production [12].
In BC, PD-1 expression levels correlate with T stage, age, and the Ki-67 proliferation index. Elevated PD-1 expression is associated with shorter overall survival and progression-free survival in BC patients, with higher expression levels observed in most BC subtypes except for Luminal A BC. Notable inhibitors targeting PD-1 in BC treatment include Pembrolizumab, Nivolumab, Atezolizumab, and Camrelizumab, among others. Attillizumab, the first immune checkpoint inhibitor approved for triple-negative breast cancer ITNBC) treatment, can be combined with chemotherapy for locally advanced unresectable cases [13]. Voorwerk demonstrated a higher objective remission rate in patients treated with the combination of nebuliuzumab and chemotherapy, along with the up-regulation of immune-related genes involved in the PD-1/PD-L1 signaling pathway and T cell-mediated immune killing [14]. Wu evaluated the feasibility of combining chemotherapy with carrilizumab and Famitinib in patients with advanced TNBC [15].

Programmed cell death 1 ligand 1(PD-L1)

The primary ligand of the immunosuppressive receptor PD-1 plays a crucial role in modulating immune responses, exerting a negative regulatory function [16]. PD-L1 is predominantly expressed on the surface of various solid tumor cells, including lung cancer, malignant melanoma, ovarian cancer, prostate cancer, and BC [17]. Apart from tumor cells, PD-L1 can also be detected in other components of the tumor microenvironment such as tumor-infiltrating lymphocytes (TILs) and macrophages [18]. Currently, immunohistochemical methods are primarily used for PD-L1 detection in BC, although standardization regarding the choice of antibodies and positive criteria remains lacking.
In BC, PD-L1 expression levels typically correlate with the presence of TILs and clinicopathological features associated with adverse outcomes. It includes younger age, ductal histology, large tumor size, estrogen receptor (ER) negativity, progesterone receptor (PR) negativity, human epidermal growth factor receptor 2 (HER2) positivity, high proliferation rate, and aggressive molecular subtypes. A meta-analysis of 37 studies examining PD-L1 expression across different BC subtypes revealed elevated expression in TNBC and HER2 amplification subtypes [19]. Several neoadjuvant therapy trials have identified high PD-L1 expression as an independent predictor of favorable pathological response at both mRNA and protein levels [20-21]. However, a study involving 870 BC patients reported that high PD-L1 expression was associated with lower disease-free survival (DFS) and metastasis-free survival (MFS), indicating a poor prognosis for these patients [22]. Conversely, another study involving 636 stage I-III BC patients found that PD-L1 mRNA expression was linked to improved recurrence-free survival (RFS) [23]. A meta-analysis focusing on Luminal A, Luminal B, HER2-based amplification, and TNBC subtypes indicated that while PD-L1 expression correlated with shorter overall survival (OS) and DFS, this association was absent within the TNBC subtype [24]. Notably, in several studies specifically targeting TNBC or basal-like patterns, PD-L1 expression predicted higher OS rates [25-27].

Cytotoxic T lymphocyte-associated antigen-4(CTLA-4)

CTLA4, a transmembrane protein expressed on both CD4+ and CD8+ T cells, functions to inhibit T cell activation through two mechanisms. Firstly, by binding to the B7 ligand on the antigen-presenting cell (APC) surface, CTLA-4 competitively inhibits CD28 co-stimulatory signals, thereby exerting an extracellular space-occupying effect. Secondly, through its intracellular YVKM motif, CTLA-4 activates downstream inhibitory enzymes such as tyrosine phosphatase-2 and protein phosphatase-2A. Tyrosine phosphatase-2 dephosphorylates the CD3 chain, attenuating T cell receptor signaling, while protein phosphatase-2A dephosphorylates protein kinase B [28]. Yu conducted a study on 130 BC patients revealed CTLA-4 expression not only in BC cells but also in tumor-infiltrating lymphocytes. Patients with high total CTLA-4 expression exhibited poorer prognosis [29]. CTLA4 blockade can directly inhibit the proliferation of tumor cells expressing high levels of CTLA-4 and induce their apoptosis. Additionally, it alleviates dendritic cell inhibition, thereby restoring dendritic cell and CTL functions [30]. Ipilimumab, a monoclonal antibody that effectively blocks CTLA-4, was developed after decades [31]. The two main anti-CTLA-4 drugs used in BC research are ipilimumab and tremelimumab. CTLA-4 expression correlates with age in BC patients, with increased expression observed in older patients [32]. Dai suggested that CTLA4 + 6230G > A mutation could effectively reduce homozygous and recessive inheritance in the Chinese population, lowering the risk of BC [33]. High CTLA-4 expression corresponds to a low fraction of activated T cells, positively correlating with patient survival [34]. Furthermore, BC patients with higher CTLA-4 expression show a significant propensity for axillary lymph node metastasis [35].

CD39/CD73

CD39, an extracellular adenosine triphosphate hydrolase, and CD73, an extracellular nucleotidase, are ubiquitous in most tissues. CD39 catalyzes the hydrolysis of extracellular adenosine triphosphate and adenosine diphosphate to produce adenosine monophosphate, subsequently converted by CD73 into adenosine, which exhibits immunosuppressive properties. Adenosine binds to adenosine receptors on effector T cells and natural killer cells, elevating intracellular cyclic adenosine monophosphate levels. This leads to the upregulation of CD25, diminishing effector T cell proliferation, reducing immune factor production, and attenuating natural killer cell activity [36].
CD73 is expressed variably in normal mammary gland and BC tissues, with markedly increased expression and activity in metastatic BC. Its expression positively correlates with tumor grade and lymph node metastasis, while inversely correlating with estrogen receptor expression [37]. Allard reported that CD73 expression is higher in TNBC compared to other subtypes. This elevated expression associated with poorer prognosis and heightened resistance to chemotherapy drugs [38].

Transmembrane glycoprotein (LAG-3)

LAG-3 ligands, which are major histocompatibility complex class II (MHC-II) molecules, interact with LAG-3 to modulate T cell activity and dendritic cell differentiation [39]. This interaction can weaken T cell function and accelerate T cell failure. Additionally, LAG-3 indirectly inhibits T cell activity by regulating the function of CD4+ CD25+ Tregs [40] IMP321, a recombinant LAG3-Ig fusion protein, binds to MHC-II on activated antigen-presenting cells (APCs), activating memory CD8+ T cells and enhancing anti-tumor activity [41]. Expression of LAG-3 on immune cells has been observed in samples from patients with malignant pleural mesothelioma [42]. Galectin-3, expressed by CD8+ T cells, also contributes to the inhibition of anti-tumor responses [43]. Studies in primary non-small cell lung cancer have shown a correlation between LAG-3+ tumor-infiltrating lymphocytes (TILs) and disease-free survival. Co-administration of anti-LAG-3 antibody with anti-PD-1 antibody (nivolumab) has been found to enhance immune tolerance and promote T cell exhaustion, demonstrating efficacy in cancer treatment [44-45].

T cell Ig and mucin domain 3 (TIM-3)

IM-3 was initially identified as a specific marker of fully differentiated T cells secreting IFN-γ, including CD4+ Th1 and CD8+ cytotoxic T cells. Many studies have revealed that TIM-3 is also expressed on the surface of other immune cells, such as Tregs, mononuclear macrophages, and dendritic cells [46].  Its main mechanism of action involves the regulation of T cell proliferation and cytokine secretion. TIM-3 can exert its inhibitory effects by directly binding to CD4+ T cells, and it can also regulate the activity of CD4+ T cells when expressed on other immune cells [47]. Additionally, TIM-3 has been found to induce the expansion of bone marrow-derived suppressor cells [48]. CD8+ T cells are pivotal for tumor cell destruction, and TIM-3 released by tumors can impair their proliferation and effector function, enabling tumors to evade immune surveillance [49].

Indoleamine 2,3 dioxygenase (IDO)

IDO functions by depleting tryptophan levels within the tumor microenvironment, thereby directly impacting T cell activity. Additionally, its metabolite, kynurenine, has been shown to induce apoptosis in T cells. IDO may also contribute to immune tolerance by promoting the differentiation of T cells into regulatory T cells (TreGs) or by directly activating mature TreGs. Chen et al. [50] reported that IDO metabolites can enhance BC metastasis, with higher IDO expression correlating with poorer prognosis, particularly in the TNBC subgroup. Furthermore, Del has demonstrated the presence of IDO not only within BC cells but also in microvesicles within the BC microenvironment, suggesting its involvement in cancer cell migration and immune evasion [51].

B and T lymphocyte attenuator (BTLA)

BTLA, a co-inhibitory molecule with an immunoglobulin-like structure, is part of the CD28 family. Its cytoplasmic region contains ITIM and ITSM similar to CTLA-4 and PD-1, which exert negative regulation on peripheral immune tolerance and response. Upon binding to its ligand, BTLA exhibits negative immunomodulatory effects. While BTLA is highly expressed on B cells at rest, its expression on T cells, PDC cells, KT cells, and natural killer cells is relatively low. Upon activation, BTLA expression decreases in B cells but increases, particularly in Th1 cells, representing a reverse interaction [52]. Despite its role in maintaining T cell survival, BTLA restricts proliferation and activity, thereby promoting peripheral immune tolerance and constraining anti-tumor immunity. Moreover, BTLA can synergistically inhibit T cell function alongside other co-inhibitory molecules like PD-1 and TIM-3 [53], solidifying its status as a pivotal T cell inhibitory receptor.

TIGIT

TIGIT, a member of the immunoglobulin superfamily, possesses an immunoreceptor tyrosine-based inhibitory motif (ITIM) and a short intracellular domain phosphorylation motif akin to the immunoglobulin tyrosine tail (ITT) [54]. TIGIT inhibitors currently in development include Vibostolimab and Tiragolumab. Tirelliumab, the primary drug for HER2-high BC treatment, often encounters resistance due to inadequate antibody-dependent cellular cytotoxicity (ADCC) triggered by natural killer (NK) cells [55]. Xu investigated the potential of TIGIT blockade in enhancing the anti-tumor response of human NK cells activated by Trastuzumab. By incubating purified NK cells with Trastuzumab-coated BC cells and adding TIGIT inhibitors, significant elevation in interferon-γ (IFN-γ) production by NK cells was observed compared to controls [56]. These findings suggested that TIGIT blockade enhances cytokine secretion in NK cells upon stimulation by Trastuzumab-coated BC cells, augmenting anti-tumor activity. Tegaserod maleate (TM), a serotonin receptor 4 agonist, demonstrates promising therapeutic effects in BC [57].

VISTA

VISTA, a type I transmembrane protein, can bind to PSGL-1 on T cells at acidic pH, resulting in the inhibition of T cell function [58]. BC tissues exhibit higher VISTA expression levels compared to adjacent normal tissues, with VISTA being the most expressed immune checkpoint in BC tissues. VSTB112 inhibits VISTA's interaction with PSGL-1 and VSIG3. BMS-767 is the sole pH-selective monoclonal antibody, inhibiting the interaction between PSGL-1 and VSIG3 specifically at a low pH of 6.0. 

Combining immunotherapy with systemic therapy (e.g., hormonal therapy, chemotherapy), radiotherapy, and local therapy (e.g., cryoablation) has demonstrated efficacy in reducing drug resistance and enhancing treatment outcomes, as supported by clinical evidence [59], and illustrated in Figure 2.

Combined application of immune checkpoint suppression and chemotherapy

Traditionally, chemotherapy was thought to suppress the immune system, leading to belief that it cannot be combine with immunotherapy. However, recent studies suggest that immunotherapy can enhance tumor cells sensitivity to chemotherapy drugs. In metastatic breast cancer cell models, researchers observed that PD-1/PD-L1 pathway blockers can enhance the activity of doxorubicin in inhibiting tumor metastasis. Combining PD-1 blocked with doxorubicin significantly promote tumor regression and prolongs survival [60].

Combined application of immune checkpoint suppression and radiotherapy

Although radiotherapy is commonly associated with immunosuppressive effects, it can activate the immune system at appropriate doses. Radiotherapy induces the recruitment of activated cytotoxic T cells to the tumor microenvironment, facilitating tumor cell destruction and immune modulation [61]. Additionally, radiation therapy can trigger systemic reactions, known as ectopic effects, which synergize effectively with immunotherapy, such as immune checkpoint blockade or adoptive cell therapy [62]. Therefore, the judicious use of radiation not only targets tumor cells locally to curb tumor growth but also induces systemic ectopic effects to impede metastasis. When combined with immunotherapy, radiation therapy yields superior outcomes compared to monotherapy.

Combined application of immune checkpoint inhibition and tumor vaccine

Breast cancer, characterized by low immunogenicity, presents challenges for immunotherapy. However, the combination of tumor vaccines with immune checkpoint inhibitors offers promising avenues to address this limitation. Petrizzo explored the efficacy of a multiple peptide vaccine (PEPT) in combination with metronomic chemotherapy (MCT) and immune checkpoint inhibitors (CI). Results indicated that compared to PEPT alone, the combinations of PEPT+MCT and PEPT+CI demonstrated significant enhancements in tumor growth inhibition, survival rates, and reduction of regulatory T cells. Particularly, the combination of PEPT+MCT+CI yielded the most favorable outcomes in these aspects [63].

The memory function inherited in immune responses, grants immunotherapy a prolonged efficacy compared to mainstream anti-tumor treatments. This make is particularly suitable for patients with advanced tumors or recurrent tumors following various adjuvant therapies. Immunotherapy exhibits broad efficacy across diverse tumor types and holds promise for evolving into a more targeted approach with fewer adverse effects, facilitating the elimination of residual tumor cells. Notably, PD-1/PD-L1 and CTLA4 inhibitors have established efficacy for treatment of BC, with ongoing clinical trials exploring newer immune checkpoint inhibitors like TIGIT, VISTA, and TIM3.
Despite significant progress, drug resistance to existing immune checkpoint inhibitors remains a common challenge and limiting patient outcomes. The current approach is to mitigate immune-related adverse reactions while optimizing immunotherapy efficacy. It can be achieved either by using combination strategies such as pairing immune checkpoint inhibitors with chemotherapy, radiotherapy, or targeted oncogene therapy have shown promise, positioning immunotherapy as a pivotal approach in breast cancer treatment. As novel targets emerge, the focus of future research extends to assessing the synergistic effects of various therapies to discover the best combinations yielding optimum clinical outcome. Additionally, there is a crucial need to investigate and identify relevant biomarkers capable of predicting tumor responsiveness to these treatment strategies, thereby augmenting their efficacy and precision. 

Acknowledgements

None.

Availability of data and materials

Data and materials are available on request from the authors.

Ethical policy

Not applicable.

Author contributions

XYZ and JW conceptualized, designed, conducted research, and wrote the first draft; XYZ contributed to the revision and figure production; KYZ provided supervision and revision of the draft.

Competing interests

The authors have no conflicts of interest regarding the publication of this paper.

Funding

None.

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