Breast cancer is a type of malignant tumor resulting from the uncontrolled proliferation of breast epithelial cells. In China, the incidence of breast cancer has been rising year by year. Tumor metastasis accounts for approximately 90% of cancer-related deaths [1]. Despite progress in understanding breast cancer progression and ongoing trials of new treatment methods, the incidence and mortality rates remain high [2]. Platelets are multifunctional cells that, upon activation by various in vivo and in vitro stimuli, undergo deformation, adhesion, aggregation, and release reactions. Their primary function is to recognize vascular lesions and initiate thrombus formation to stop bleeding. This unique characteristic of platelets also contributes to cancer development and progression. The ability of platelets to recognize other cells and neighboring platelets enables them to interact with circulating tumor cells. Receptor recognition and factor-mediated crosstalk between tumor cells and platelets stimulate platelet activation, factor release, and aggregation, thereby promoting tumor cell survival and cancer progression [3]. Therefore, this study explores the correlation between platelet function and tumor staging as well as tumor metastasis.

According to the World Health Organization’s International Agency for Research on Cancer (IARC), the latest global cancer burden data for 2020 was released. Globally, new breast cancer cases reached 2.26 million, surpassing the 2.2 million cases of lung cancer, making breast cancer the world’s leading cancer [4]-[6]. Breast cancer is a type of malignant tumor resulting from the uncontrolled proliferation of breast epithelial cells. In China, the incidence of breast cancer has been rising year by year, with over 300,000 women diagnosed annually. This upward trend is particularly evident in eastern coastal regions and economically developed large cities. Despite continuous advances in understanding breast cancer progression and ongoing trials of new therapeutic approaches, the incidence and mortality rates remain alarmingly high [7]-[9]. It has been established that even decades after diagnosis and resection of the primary tumor, 25% - 50% of breast cancer patients will ultimately develop fatal metastasis. Certain histological subtypes and molecular markers of breast cancer are considered to hold strong predictive value. For instance, ER-, PR-, and HER-2-negative cancers, known as “triple-negative” breast cancer, are associated with significantly elevated risks of progression and metastasis [10][11]. Unfortunately, patients with metastatic disease typically have a poor prognosis, with an average 5-year survival rate of approximately 25% [12][13].

Treatment regimens used in clinical practice can control the growth of primary tumors. However, these methods are less effective in preventing recurrence and managing breast cancer metastasis. The interaction between tumor cells and platelets is a prerequisite for successful hematogenous metastatic dissemination. Once tumor cells enter the bloodstream, they immediately activate platelets to form a permissive microenvironment. Platelets shield tumor cells from shear forces and attacks by natural killer (NK) cells, recruit bone marrow-derived cells through the secretion of chemokines, and mediate the adhesion of tumor cell-platelet emboli to the vascular wall. Subsequently, platelet-derived growth factors endow tumor cells with a mesenchymal-like phenotype and disrupt capillary endothelial barriers to accelerate extravasation into distant organs. Finally, growth factors secreted by platelets stimulate the proliferation of tumor cells into micrometastatic foci [14]. Platelets play a crucial role in hemostasis. Due to the excessive release of factors upon activation, platelet function is also linked to tumor growth, particularly through effects on angiogenesis. It is now widely recognized that the primary role of platelets in poor outcomes for cancer patients occurs during the hematogenous dissemination of cancer cells. Platelets have been demonstrated to confer resistance to circulating tumor cells (CTCs) against NK cell attacks and shear forces, thereby promoting CTC survival in the bloodstream [15]. Platelet membrane surfaces express specific glycoproteins, known as molecular markers specific for activated platelets, with the most important being the platelet membrane glycoprotein GPIIb/IIIa fibrinogen receptor (PAC-1) and P-selectin (P-selectin, CD62P), as well as CD31, CD63, CD41, CD61, and CD62. Studies have found that platelet activation markers (CD41+CD62P+%, CD61+CD62P+%, CD41+CD61+CD62P+%) in the metastatic group of breast cancer patients were significantly higher than those in the early stage group and the healthy control group, while there were no significant differences between the non-metastatic group and the healthy control group. This result suggests that platelet activation is not a universal phenomenon in breast cancer occurrence but specifically participates in the metastatic process of breast cancer. The potential mechanism may involve: activated platelets promoting epithelial-mesenchymal transition (EMT) in tumor cells through the release of cytokines such as TGF-β and VEGF, thereby enhancing their invasive and metastatic capabilities; at the same time, platelets can adhere to circulating tumor cells to form aggregates, helping tumor cells evade host immune surveillance and shear force damage [16]. This study also found that CD8+PD-1+% expression was highest in the metastatic group, followed by the non-metastatic group, and lowest in the healthy control group, showing a gradually increasing trend. This result is consistent with the research by Han Yinli et al. [17], reflecting that as breast cancer progresses, PD-1 expression on CD8+ T cells gradually increases, and the degree of T cell immune exhaustion intensifies. As an inhibitory receptor on the T cell surface, PD-1’s high expression suppresses T cell cytotoxic function, allowing tumor cells to evade immune clearance. In this study, CD8+PD-1+% in the metastatic group reached as high as 48.72%, indicating that immune exhaustion is more severe in advanced breast cancer and may be one of the key reasons for resistance to immunotherapy. Further correlation analysis showed a significant positive correlation between CD41+CD62P+% and CD8+PD-1+% (r = 0.586, P = 0.004), suggesting a possible synergistic effect between platelet activation and CD8+ T cell immune exhaustion. Activated platelets may induce upregulation of PD-1 expression on CD8+ T cells through direct contact or secretion of soluble factors (such as TGF-β and IL-10), thereby weakening anti-tumor immunity; conversely, the immune-exhausted microenvironment may further promote platelet activation, forming a vicious cycle that collectively drives the metastatic process of breast cancer. Studies have found that tumor cells induce platelet activation through the release of tissue factor, thrombin, and matrix metalloproteinases. Activated platelets express a large number of glycoprotein molecules on their membrane surface and adhere around tumor cells to form tumor cell-platelet complexes (TCIPA), providing the possibility for tumor cell survival in the vascular system and successful metastasis [18]. Multivariate logistic regression analysis confirmed that both CD41+CD62P+% and CD8+PD-1+% are independent predictors of breast cancer metastasis. Multivariate logistic regression analysis indicated that both CD41+CD62P+% and CD8+PD-1+% were independently associated with locally advanced/metastatic status in this study cohort, suggesting that combined detection of platelet activation markers and CD8+PD-1+% may help identify patients at higher risk of disease progression.

However, this study has the following limitations: First, the sample size is relatively small, particularly with only 16 cases in the metastatic group, which may impact statistical power; thus, the conclusions require further validation through expansion of the sample size. Second, as a single-center cross-sectional study, it lacks dynamic follow-up data, making it impossible to establish causal relationships between changes in indicators and the timing of metastasis. Third, other platelet function indicators, such as platelet-leukocyte aggregates, were not assessed, limiting the comprehensive evaluation of platelet function. Future research should involve larger sample sizes and prospective cohort studies for validation.

Patients in the breast cancer metastasis group showed significantly elevated platelet activation markers (CD41+CD62P+%, CD61+CD62P+%, and CD41+CD61+ CD62P+%) as well as CD8+PD-1+% expression levels. These markers were positively correlated with each other and were all identified as exploratory associations with breast cancer. Combined detection demonstrates high predictive efficacy for metastasis and may serve as a potential reference indicator for monitoring disease progression in breast cancer patients, though further validation with a larger sample size is needed.

Self-Funded Research Project of the Health Commission of the Autonomous Region: Z-N20231846.

*First author.

^#Corresponding author.