Tumor-mediated remote regulation of peripheral blood platelets.

Introduction and research background
The role of platelets in blood coagulation and vascular repair is well known. However, platelets' regulatory function in the emergence and growth of malignant tumors has garnered significant attention in recent years, and they are even thought to be significant mediators of the advancement of cancer. The precise manner in which tumor cells impact peripheral platelets are still a significant mystery, despite the fact that numerous studies have shown the complex interaction between malignancies and platelets. This review systematically summarizes the latest research progress on how tumors regulate the quantity, volume, composition, and activation state of peripheral blood platelets through various mechanisms.

The regulation of tumors on peripheral platelets
In recent years, extensive attention has been given to the systemic impact of tumors on peripheral blood platelets and their key role in cancer progression. Tumor cells and the unique microenvironment they shape can regulate platelets in the peripheral blood circulation across domains through a variety of complex and intertwined mechanisms and pathways. This regulation is reflected in multiple levels: (1) quantity regulation; (2) volume regulation; (3) composition regulation; (4) function regulation (Fig. 1). Tumor cells can directly or indirectly induce changes in the quantity, volume, composition, and function of peripheral platelets through multiple pathways, and these pathways will be explained one by one in this review.

Tumors regulate the number of peripheral platelets across domains
The results and mechanisms by which tumor cells regulate the number of peripheral platelets are diverse. Tumor cells can regulate the increase or decrease in the number of peripheral platelets in various ways (Table 1).

An increase in the peripheral platelet count
When the number of peripheral blood platelets exceeds 450 × 109/L (or the platelet count is > 450,000 per cubic millimeter), thrombocytosis occurs. Thrombocytosis frequently occurs in cancer patients (10% to 57%) (Sierko and Wojtukiewicz 2007). Among ovarian cancer, lung cancer, and gastric cancer patients, those with hematogenous metastasis and recurrence have a relatively high incidence of thrombocytosis. Specifically, the incidence of thrombocytosis in stage IV ovarian cancer is as high as 65% (Li et al. 2024). Thrombocytosis is present in 57% of non-small cell lung cancer patients, and its incidence in stage III-IV patients is significantly greater than that in early-stage patients (I-II) (Pedersen and Milman 2003).

Tumors remotely regulate platelet count through cytokines
In the normal hematopoietic process, platelet production can be stimulated at various levels, primarily through thrombopoietin (TPO) and its receptor (Lin et al. 2014). Compared with patients without thrombocytosis, those with thrombocytosis present significantly elevated levels of thrombopoietin and interleukin-6 (IL-6) in their plasma. Interleukin-6, a self-secreted growth factor, is overproduced in various malignant tumors, including gastrointestinal cancer, renal cell carcinoma, prostate cancer, epithelial ovarian cancer, and lung cancer, as well as Kaposi's sarcoma and glioblastoma multiforme (Kaser et al. 2001). Tumor-derived interleukin-6 has been demonstrated to promote thrombopoietin synthesis in the liver in mice models, which may be a mechanism for tumor-induced thrombocytosis. Thrombocytosis in patients is also tightly linked to hepatic thrombopoietin and interleukin-6 generated from tumors. Studies have demonstrated that in tumor-bearing mice, thrombopoietin silencing with siRNA eliminates about 50% of thrombocytosis, interleukin-6 silencing with siRNA eliminates about 30% of thrombocytosis, and the combination of interleukin-6 and thrombopoietin with siRNA is the most effective, totally eliminating thrombocytosis. In terms of treatment, anti-IL-6 antibody therapy significantly reduces platelet counts in tumour-bearing mice and, in a small clinical trial involving 18 patients with epithelial ovarian cancer, was associated with reduced platelet counts (Coward et al. 2011). Moreover, neutralizing interleukin-6 significantly enhanced the therapeutic effect of paclitaxel in a mouse model of ovarian epithelial cancer. With the use of antiplatelet antibodies, the platelet count in tumor-bearing mice was reduced by half, which significantly decreased tumor growth and angiogenesis. These findings support the existence of a paracrine circuit (Fig. 2) (Stone et al. 2012). Tumor-induced peripheral thrombocytosis is primarily attributed to interleukin-6 produced by tumor cells, which is released into the bloodstream and stimulates the liver to produce thrombopoietin. TPO then binds to the TPO receptor c-Mpl on megakaryocytes, stimulating their growth and maturation in the bone marrow. Mature megakaryocytes subsequently form platelet precursors that extend and eventually shed to form platelets (Li et al. 2024). The increase in platelet count further promotes tumor growth, forming a positive feedback loop (malignant tumors produce cytokines such as IL-6, which stimulate thrombocytosis, while tumor cells themselves directly or indirectly activate platelets). Conversely, an increased number of activated platelets further promotes tumor growth and metastasis, leading to greater stimulation of platelet levels and activity (Lin et al. 2014)). Therefore, we speculate that targeting these cytokines, either directly or indirectly, may have therapeutic potential for combating paraneoplastic thrombocytosis (Stone et al. 2012).
In addition, studies have shown that other tumor-related cytokines, such as granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), interleukin-1 (IL-1), and vascular endothelial growth factor [VEGF], also promote platelet production in cancer. The Specific Mechanism Is as Follows:Granulocyte Colony-Stimulating Factor (G-CSF) acts directly on bone marrow hematopoietic stem cells, promoting the proliferation and differentiation of megakaryocyte precursors and accelerating the maturation of megakaryocytes. At the same time, it can indirectly upregulate the activity of Thrombopoietin (TPO), enhance the proliferation-promoting effect of TPO on megakaryocytes, and ultimately increase the release of platelets.Interleukin-1 (IL-1) indirectly regulates the development of megakaryocytes by activating bone marrow stromal cells and inducing them to secrete TPO and other hematopoietic growth factors.On one hand, Vascular Endothelial Growth Factor (VEGF) improves bone marrow angiogenesis, optimizes the oxygen and nutrient supply in the hematopoietic microenvironment, and provides support for the proliferation of megakaryocytes; on the other hand, it directly binds to VEGF receptors on the surface of megakaryocytes, promoting their migration, maturation, and platelet release. Meanwhile, it can enhance signal transduction by upregulating the expression of TPO receptors. (Wojtukiewicz et al. 2017; Yu et al. 2021; Catani et al. 2020; Hufnagel et al. 2020; Chaudhary et al. 2022). The presence of these humoral factors and cytokines provides new research directions and potential therapeutic strategies.

Tumors remotely regulate platelet numbers through amino acid metabolites
Factors originating from tumors are believed to regulate the peripheral blood platelet count in cancer patients, leading to an increase. Platelets and red blood cells both originate from a common precursor cell, the megakaryocyte–erythroid progenitor (MEP) (Akashi et al. 2000; Iwasaki and Akashi 2007). Numerous transcription factors, including GATA1, GATA2, Runx1, TAL1, FLI1, MYB, and KLF1, play a role in the differentiation of megakaryocytes into erythroblasts (Tijssen et al. 2011; Bianchi et al. 2010; Graf 2019; Pimkin et al. 2014). RUNX1 and GATA1 are particularly crucial for the differentiation of megakaryocytes and erythroblasts, respectively (Zhou et al. 2023). We know that megakaryocytes need to undergo endoreplication and cytoplasmic differentiation to form platelet precursors. If differentiation is impaired, it will lead to insufficient platelet production, abnormal platelet morphology, and congenital defects in basic functions. At the same time, the α-granules, dense granules, and active molecules of platelets are all synthesized by megakaryocytes and packaged in a directional manner. Metabolic disorders of megakaryocytes can result in the deficiency, excess, or structural abnormality of these contents.
Kynurenine (Kyn) is a key endogenous intermediate in the tryptophan metabolic pathway. It is a bioactive molecule with significant immune regulatory and neuroactive effects, influences various neurological disorders, and serves as a precursor for NAD+ synthesis. Kynurenine is not an amino acid. Tumor cells release canine kynurenine, which activates the aryl hydrocarbon receptor (AhR)-runx-related transcription factor 1 (AhR-RUNX1) axis, leading to a shift in cancer patients' megakaryocyte-to erythroid progenitor differentiation toward megakaryocytes (Fig. 3) (Graf 2019; Pimkin et al. 2014; Zhou et al. 2023). Tryptophan, an essential amino acid, is widely utilized by tumor cells, partly because the Myc oncogene protein can induce the expression of the tryptophan transporters SLC7A5 and SLC1A5 (Venkateswaran et al. 2019). Consequently, tumor cells absorb and catalyze tryptophan, producing Kynurenine (Kyn) through indoleamine 2,3-dioxygenase (IDO). As tumors grow, a large amount of Kynurenine (Kyn) from tumor cells is released into the periphery and taken up by myeloid progenitor cells (MEPs) via the transporter SLC7A8. In the cytosol, Kyn binds and activates AhR, causing it to translocate to the nucleus, where AhR transactivates RUNX1, regulating MEP differentiation into megakaryocytes. Additionally, activated AhR upregulates SLC7A8 in MEP cells, inducing positive feedback. Importantly, MEP differentiation regulated by Kyn-Ahr RUNX1 was demonstrated in both humanized mice(including those of melanoma, colon cancer, and breast cancer, among others)and cancer patients, and an increase in megakaryocyte production increased platelet numbers (Zhou et al. 2023). These findings provide a potential therapeutic strategy for the prevention of thrombocytosis. Meanwhile,the insight that platelet precursors (megakaryocytes) are affected by kynurenine has made us aware of the inadequacy of our current research in the areas of kynurenine's downstream effects on platelet bioenergetics, mitochondrial function, and signal transduction—paving the way for future research directions.

Peripheral blood platelet count decreased
Thrombocytopenia is a condition in which the platelet count in the blood falls below the normal range (less than 100 × 109/L), potentially increasing the risk of bleeding. Mild thrombocytopenia generally does not have direct clinical effects. However, spontaneous bleeding is a major cause of death in adults with a platelet count less than 5 × 109/L(Cines and Blanchette 2002), which warrants increased attention.

Indirect regulation of platelet reduction by tumors
According to previous studies, approximately 10% to 38% of patients with solid tumors experience thrombocytopenia (Shaw et al. 2021). In liver cancer staging systems such as the BCLC system, the incidence of thrombocytopenia is significantly greater in advanced stages (BCLC, C/D) (Tellapuri et al. 2018). The widespread dissemination and tissue infiltration of tumors can activate the coagulation system, leading to disseminated intravascular coagulation (DIC). This process involves the deposition of platelets and fibrin within blood vessels, resulting in relative thrombocytopenia in the peripheral blood (consumptive thrombocytopenia). Compared with other clinical conditions, the clinical course of DIC in patients with malignant tumors is less severe. Diseases that progress more slowly may remain asymptomatic. Continuous consumption can lead to a decrease in platelet levels (Levi 2019, 2018). As long as liver function remains intact, the synthesis of coagulation factors can mask ongoing chronic coagulation protein consumption. In most patients, thrombocytopenia is the most significant sign of ongoing DIC (Hitron et al. 2011). The combination of decreased platelet count (PLT) and increased mean platelet volume (MPV) has important indicative value for consumptive thrombocytopenia (CTP). However, it cannot be used alone to quantify the diagnostic probability, and a comprehensive judgment must be made in conjunction with clinical scenarios and other indicators. This also provides a broader field for future medical research.
Research indicates that other factors contribute to thrombocytopenia in patients with common tumors. The prolonged treatment required by these patients can contribute to thrombocytopenia, including chemotherapy-induced thrombocytopenia (CIT). There is growing guidance on CIT management, but evidence is limited and practice varies by regimen and cancer type.It may be caused by the disease itself or one of its symptoms, but the most common cause is chemotherapy, which suppresses bone marrow (BM) (Gao et al. 2023a). Early clinical trials have shown that 10% to 68% of patients with solid or blood cancers experience CIT (Hitron et al. 2011). Additionally, cytotoxic drugs often inhibit normal hematopoiesis. CIT is characterized by an increase in platelet clearance by mononuclear phagocytes, which is typically mediated by immune mechanisms involving drug-dependent antibodies, and can also lead to direct destruction of platelets (Curtis 2014; Aster et al. 2009). This condition, known as drug-induced immune thrombocytopenia (DITP), is not uncommon but can be challenging to diagnose. Current studies have shown that a decrease in platelet count can also affect platelet function. For instance, platelet dysfunction in cancer patients with thrombocytopenia (low platelet count) directly stems from impaired mitochondrial activity, which is manifested as a reduction in oxidative phosphorylation (OXPHOS) and a decrease in membrane potential (P < 0.001). Perhaps in future research and treatment, modifying mitochondrial activity could also reverse the health status of cancer patients (Baaten et al. 2018).

Direct regulation of platelet reduction by tumors
Tumors also play a direct role in the regulation of thrombocytopenia. Malignant tumor cells can directly infiltrate the bone marrow, disrupting the normal hematopoietic microenvironment and leading to impaired hematopoietic function. For example, bone marrow biopsies from patients with persistent severe thrombocytopenia following PRRT treatment for neuroendocrine tumors all show extensive tumor cell infiltration (Naveed Ahmad et al. 2022). Additionally, in hematological tumors, such as acute megakaryocytic leukemia (AMKL), bone marrow fibrosis and tumor cell infiltration lead to platelet production disorders (Penchansky et al. 1989). Tumor cells can also inhibit megakaryocyte production by secreting inhibitory cytokines such as TGF-β and TNF-α. The hepatopathy-thrombocytopenia syndrome (HTS) that occurs in Wilms' tumor patients after treatment with actinomycin D may be related to this mechanism (Oosterom et al. 2023).

Tumors regulate the volume of peripheral blood platelets across domains
Platelet parameters, as simple and easily accessible hematological indicators, have become a focal point in clinical research because of their associations with tumor prognosis. In particular, the MPV not only reflects the activation state of platelets but is also closely linked to inflammatory and metabolic diseases, indicating potential prognostic value in various tumors (Li et al. 2014) (Fig. 4). Tumor cells can also regulate the volume of peripheral platelets in various ways (Table 2). Studies have shown that MPV is associated with multiple types of cancer, including lung, colon, thyroid, and renal cell carcinoma (Yu et al. 2017; Yun et al. 2017).

Peripheral blood platelets are enlarged

Tumors remotely regulate platelet volume through cytokines
An elevated MPV in lung cancer patients is associated with advanced clinical stages (stages III to IV) and is significantly linked to poor survival (Detopoulou et al. 2023). As previously discussed, the paracrine pathway leads to increased levels of interleukin-6 and thrombopoietin in the body, which in turn increases platelet counts. Additionally, MPV has been found to be positively correlated with the levels of thrombopoietin and interleukin-6, which regulate the proliferation of megakaryocytes (Martin et al. 1983). Therefore, it is reasonable to infer that this is one of the mechanisms by which tumors cause an increase in platelet volume. Tumor cells release kynurenine (Kyn), which activates AhR, promoting the differentiation of megakaryoblastic progenitor cells (MEPs) toward megakaryocytes and reducing erythroid differentiation. This process may also contribute to the enlargement of platelets (Stone et al. 2012).

Tumors remotely regulate platelet volume through tissue factors
In addition, the MPV also increases in patients with colon cancer. This may be due to mediators such as tissue factor (TF) and ADP in the tumor microenvironment, which can activate platelets, causing them to release proinflammatory and growth factors (such as PDGF and TGF-β), further increasing platelet activation and leading to an increase in volume (Palacios-Acedo et al. 2022).
The increase in platelet volume in tumor patients carries considerable biological significance. On one hand, it reflects the accelerated renewal driven by faster platelet consumption: chronic inflammation and coagulation activation induced by tumors continuously deplete mature platelets in the circulation. In response, the body activates a compensatory mechanism to shorten the platelet production cycle in the bone marrow, allowing more "young platelets" to enter the bloodstream. On the other hand, the release of immature platelets serves as a crucial supplement: cytokines such as IL-6 (Interleukin-6) and TNF-α (Tumor Necrosis Factor-α) secreted by tumors stimulate bone marrow stromal cells to reshape the hematopoietic microenvironment, prompting the bone marrow to release immature platelets in advance. This indirectly indicates that the release of large platelets is not only a manifestation of the body's compensation but also a stress response of the body to stimulation (Kurt et al. 2024).

The volume of peripheral blood platelets is reduced

Tumors indirectly regulate platelet volume
On the other hand, tumors can also lead to a reduction in the peripheral blood platelet mean corpuscular volume (MPV). For example, patients with renal cell carcinoma have a significant decrease in MPV, which is positively correlated with TNM stage. In patients with stage III-IV renal cell carcinoma, the MPV is approximately 1.2-fold lower than that in stage I-II patients (P = 0.017) (Detopoulou et al. 2023). The mechanism behind this reduction in MPV may involve an increased platelet count, which leads to increased CD40L production and promotes inflammatory responses (Refaai et al. 2011; Kapur and Semple 2016; Stokes and Granger 2012). Under inflammatory conditions, the increased degradation of large platelets may contribute to the reduction in MPV, possibly because larger platelets are more sensitive to stimulation and are more likely to be selectively degraded (Sun, et al. 2018). This indirect regulation of peripheral blood platelet volume by tumors is a potential mechanism.

Tumors directly regulate platelet volume
In addition, studies have shown that the volume of platelets in patients with metastatic breast cancer is reduced, which may be associated with immune suppression or metabolic disorders in the tumor microenvironment. Research has shown that a decrease in MPV is independently linked to liver metastasis, and this association is more pronounced in postmenopausal HER2+ or triple-negative breast cancer patients (Li et al. 2019). Furthermore, studies have indicated that the average platelet volume in cervical cancer patients is also reduced. The molecular mechanisms linking cervical cancer to the reduction in MPV are not yet fully understood. The underlying mechanism may involve the dysregulation of bone marrow cells (including megakaryocytes), which could lead to changes in the MPV and Platelet Distribution Width(PDW) (Shen et al. 2017). As previously discussed, tumors can directly infiltrate the bone marrow, thereby inhibiting normal bone marrow hematopoietic function. Therefore, it is reasonable to suspect that dysregulation of bone marrow cells (including megakaryocytes) may indeed cause changes in the MPV and PDW.
In summary, the changes in platelet count (PLT) and mean platelet volume (MPV) vary across different tumor types and disease stages. For example, in digestive system tumors (including gastric cancer, colorectal cancer, and liver cancer), most cases in the advanced stage show elevated PLT and decreased MPV. This is attributed to tumor-derived thrombopoietin-like factors that lead to the release of immature platelets. Some patients with advanced tumors or metastases may experience decreased PLT due to bone marrow infiltration. Regarding lung cancer, elevated PLT is common in non-small cell lung cancer (NSCLC) and is positively correlated with tumor burden. Advanced small cell lung cancer (SCLC) is prone to decreased PLT, often associated with bone marrow metastasis or chemotherapy effects, and MPV usually increases as PLT decreases. For patients, if platelet count and morphology can be determined, it may be possible to administer diagnostic treatment and help them seize the golden window for therapy (Sandfeld-Paulsen et al. 2023; Senturk et al. 2025; Chen et al. 2021).

Tumors regulate peripheral blood platelet components across domains
Stimulatory factors secreted by tumor cells, such as the platelet agonists adenosine diphosphate (ADP) (Egan et al. 2011) and IgG (Miao et al. 2019) or functional proteins and RNA, lead to significant changes in the proteome and transcriptome of platelets (Calverley et al. 2010; Sabrkhany et al. 2018) (Table 3).

Changes in the proteome of platelets
Although platelets are anucleate, they can alter the splicing of select precursor mRNAs and translate existing mRNAs into proteins upon activation (Denis et al. 2005; Weyrich et al. 1998). Recent studies in premetastatic mouse models of breast and prostate cancer have shown that circulating platelets actively take up tumor-derived proteins, leading to increased levels of platelet-derived growth factor (PDGF), TGFβ, and matrix metalloproteinase 1 (MMP1) (Kerr et al. 2013; Kuznetsov et al. 2012) in platelets. Studies have also shown that the levels of platelet-derived growth factors (VEGF and PDGF) in colorectal cancer patients are elevated (Peterson et al. 2012), likely due to their internalization from plasma. Kerr et al. demonstrated that platelets absorb various tumor-secreted proteins that promote bone renewal, including transforming growth factor b-1 and matrix metalloproteinase 1. These proteins may be stored in platelet α granules and released into the bone microenvironment (Kerr et al. 2013). However, the mechanisms behind these changes in platelets remain unclear and require further investigation.

Changes in the platelet RNA group
With advancements in molecular biology, researchers have discovered that despite lacking a nucleus, platelets retain functional RNAs such as mRNAs, miRNAs, and circRNAs. These RNAs can undergo selective splicing and protein translation upon activation (Zhang et al. 2018). More strikingly, the tumor microenvironment significantly alters the RNA composition of platelets (Krishnan and Thomas 2022).
The changes in platelets induced by tumors are closely linked to the systemic and local responses associated with tumor growth, altering their RNA profiles. Tumor RNA can also be actively transferred; tumor cells release vesicles (sEVs) that carry specific RNAs, such as mutant mRNAs or noncoding RNAs, which transfer tumor-derived RNA to platelets. For example, glioblastoma cells transfer EGFRvIII mutant RNA to platelets, whereas prostate cancer cells transfer PCA3 RNA (Best et al. 2015). Once they are absorbed by platelets, these RNAs form a tumor-specific RNA profile. Additionally, the reprogramming of platelet function can be triggered by inflammatory factors, growth factors, or metabolic products in the tumor microenvironment, which activate platelets and induce the selective splicing of pre-mRNAs, leading to the production of abnormally mature RNAs that are translated into oncogenic proteins. For example, TGF-β secreted by tumor cells can increase the expression of RNA related to invasion and metastasis in platelets (Veld, et al. 2022). Studies have shown that detecting changes in platelets induced by tumors can accurately distinguish 228 patients with local and metastatic tumors from 55 healthy individuals with 96% accuracy. In six different types of tumors, the location of the primary tumor can be correctly identified with 71% accuracy through mRNA sequencing of 283 platelet samples, confirming the diagnostic potential of these platelets (Best et al. 2015). The characteristics of the transcriptome include (1) changes in the expression levels of specific mRNAs, such as VEGF and PDGF; (2) differential expression of noncoding RNAs, such as miR-1246 and circR4; (3) alterations in RNA modification patterns, such as m6A; and (4) changes in the proportion of alternative splicing variants (Otles et al. 2022; Oudejans et al. 2021). These changes not only indicate the presence of tumors but also may be involved in various aspects of tumor progression, providing new targets and markers for cancer diagnosis and treatment.

Tumors regulate peripheral platelet function across domains
Studies have shown that tumors alter the phenotype of bone marrow stromal cells and reshape the microenvironment by secreting factors (such as IL-6, TNF-α, and TGF-β), thereby affecting platelet production and platelet function (Braun et al. 2021). In previous studies, tumor patients exhibit a higher coagulation status, which may be associated with increased tissue factors and abnormal coagulation factors (Liu et al. 2022). Tumor cell-induced platelet aggregation (TCIPA) is a phenomena where tumor cells stimulate platelet aggregation to promote platelet activation (Jurasz et al. 2004). This process involves multiple molecular mechanisms, including direct contact-dependent activation: tumor cells express various platelet activation molecules on their surface, such as tissue factor (TF), selectin ligands, and integrins. For example, prostate cancer cells express functional αIIbβ3 integrin, which facilitates binding with platelet GPIIb-IIIa (Trikha et al. 1996). The cancer-derived αIIbβ3 and platelet-derived GPIIb-IIIa (which are actually the same molecule) interact through multiple mechanisms to form a "lethal alliance" that promotes tumor metastasis. The αvβ3 on the surface of melanoma cells and the αIIbβ3 on platelets form a complex via fibrinogen bridging, which facilitates the adhesion of tumor cells to the vascular wall under blood flow shear stress. The anti-αIIbβ3 antibody and anti-αvβ3 antibody (CD51) can respectively inhibit the adhesion between tumor cells and platelets (Pijning and Hogg 2025). In addition to this,TF activates the coagulation cascade to produce thrombin, a key trigger for TCIPA. Studies have shown that silencing tumor TF expression can significantly inhibit platelet aggregation and metastasis (Liu et al. 2019). Soluble mediator-dependent activation: Tumor cells secrete lipid mediators such as ADP, thromboxane A2 (TXA2), and 12-hydroxyscine eicosan-3,5,8,10-tetraenoic acid (12-HETE) to activate platelets. In particular, many tumor cells express platelet-type 12-lipoxygenase, which produces 12(S)-HETE, promoting platelet aggregation and the adhesion of tumor cells (Chen et al. 1994). There is literature indicating that extracellular vesicle-mediated activation: Small extracellular vesicles (tumor-derived sEVs) from tumors are taken up by platelets through a CD63-dependent mechanism, transmitting signals that promote aggregation. These vesicles carry RNA (such as miR-1246) and proteins (such as PDPN) that can significantly increase platelet reactivity (Dudiki et al. 2023; Kanlikilicer et al. 2018). In addition to being linked to an increased risk of thrombosis, TCIPA is thought to encourage angiogenesis and metastasis, which has a detrimental effect on patient prognosis and survival rates (Ferroni et al. 2011; Olsson and Cedervall 2018). Tumors induce platelet activation by interacting directly with platelets or by releasing procoagulant factors (such as tissue factor (TF), podoplanin (PDPN), ADP and tumor EVs (exosomes derived from cancer cells) (Abdol Razak et al. 2018; Geddings and Mackman 2013; Chen et al. 2015). Tumor-derived exosomes activate platelet integrin αIIbβ3 in a concentration- and time-dependent manner. Interestingly, when catabolic extracellular vesicles (cancers EVs) are present, platelet aggregation tests using ADP show that these vesicles have a synergistic effect on ADP-induced platelet aggregation (Dudiki et al. 2023), thereby accelerating platelet activation and thrombus formation. Tumors stimulate an increase in platelet numbers, and the aggregation and activation of platelets lead to thrombus formation, posing a significant survival risk for cancer patients.

Tumor-induced platelet activation and its role in tumor proliferation and invasion
Apart from their conventional functions in hemostasis and thrombosis, platelets are also thought to be important mediators in malignant malignancies. Through a variety of stimuli, tumor cells activate platelets, and through a variety of mediators, platelets support intracellular signaling, tumor cell proliferation, and the epithelial-mesenchymal transition (EMT). Tumor growth and invasion are significantly influenced by the interaction between platelets and tumor cells (Haemmerle et al. 2018; Yu et al. 2014). Platelet microvesicles (PMPs) are granules that express membrane receptors and cytoplasmic components when platelets are stimulated or subjected to high shear stress. There is growing evidence that PMPs directly contribute to the formation and proliferation of cancerous cells. PMPs have the ability to stimulate chemotaxis in a variety of hematopoietic cells and improve their fibrin adhesion affinity (Aharon and Brenner 2009). PMPs express multiple proteins and chemokine receptors that can be transferred to surrounding cell membranes, including those of malignant cells, thereby increasing their invasiveness (Barry and FitzGerald 1999; Barry et al. 1998; Barry et al. 1997). In intrahepatic cholangiocarcinoma (iCCA), the interaction between platelets and tumor cells significantly enhances the EMT process, which is characterized by the downregulation of E-cadherin and the upregulation of vimentin and n-cadherin. Platelet coculture experiments revealed that the migration and invasion of tumor cells are significantly enhanced, a phenomenon further validated in in vivo models. Platelets store and release angiogenic factors such as VEGF and PDGF, promoting tumor angiogenesis. Moreover, platelets form 'platelet‒CTC clusters' by encapsulating circulating tumor cells (CTCs), protecting CTCs from shear forces in the bloodstream and facilitating their extravasation to distant organs (Yao et al. 2024). Clinical data support platelet-related parameters as prognostic markers, and strategies targeting tumor-affected platelets (such as antiplatelet drugs and pathway inhibitors) show significant therapeutic potential. Future research should further explore the precise regulatory mechanisms of platelets in specific tumor types to optimize combined treatment regimens.

The Impact of Platelet-Secreted Factors on Cancer Treatment
Platelets directly support the proliferation and survival of tumor cells by releasing growth factors such as TGF-β, VEGF, and PDGF. They also release exosomes and microparticles, which transmit oncogenic signals to tumor cells and enhance the latter's stemness and invasive capabilities (Zhong et al. 2025; Elaskalani et al. 2017). TGF-β is known as the "chief executive officer" of immunosuppression, and it can cause T-cell suppression: downregulating the secretion of IFN-γ and TNF-α by CD8 + T cells and inducing the exhausted phenotype of T cells; NK cell inactivation: specifically reducing the expression of NKG2D, thereby blocking the recognition and killing of tumor cells by NK cells; antigen presentation disorders: inhibiting the maturation and function of dendritic cells, reducing the expression of MHC-I molecules, and blocking antigen presentation; and recruitment of immunosuppressive cells: promoting the differentiation of M2-type macrophages, MDSCs (Myeloid-Derived Suppressor Cells), and TANs (Tumor-Associated Neutrophils) to form an "immune desert" microenvironment. In addition, TGF-β induces the expression of PD-L1 in both tumor cells and immune cells, forming an "immunosuppressive positive feedback loop" (Kopp et al. 2009).
VEGF and PDGF released by platelets promote the abnormal proliferation of tumor blood vessels, increase vascular permeability and interstitial fluid pressure, and impede drug penetration. Activated platelets secrete fibrinogen and coagulation factors, forming a "fibrin barrier" around tumors, which reduces the delivery rate of chemotherapeutic drugs (Cai et al. 2025).
Platelet-targeted therapeutic strategies (such as aspirin and ticagrelor) can simultaneously enhance the efficacy of immunotherapy and chemotherapy, achieving a synergistic effect of "1 + 1 > 2". Platelet-related biomarkers (such as PLR (Platelet-to-Lymphocyte Ratio) and platelet PD-L1) can serve as novel biomarkers for predicting the response to immunotherapy and guiding individualized treatment (Hinterleitner et al. 2021; Pandey et al. 2014).

Application of tumor cross-regulation of platelets in clinical diagnosis and treatment

Application of platelet-related biomarkers from tumor sources in tumor diagnosis and prognosis evaluation
Currently, platelet-related biomarkers are a hot topic in research. The tumor microenvironment alters the RNA and proteome of platelets by releasing soluble factors (such as IL-6 and TGF-β) and extracellular vesicles, resulting in the formation of tumor-influenced platelets (Bravaccini et al. 2024). These changes in the transcriptome and proteome of platelets reflect the molecular characteristics of tumors, making them potential diagnostic and prognostic markers (Gao et al. 2023b). Platelet proteomics studies have revealed that the N-glycosylation patterns of certain glycoproteins (such as C3 and ITGB3) in liver cancer patients significantly differ and can serve as potential diagnostic markers (Xie et al. 2025). For example, a large-scale PCA3 analysis of platelets from 32 prostate cancer patients revealed that 69% of the patient samples tested positive for this marker, whereas all the control samples were negative. Importantly, two months after prostatectomy, PCA3 was not detected in most patients. These findings suggest that PCA3 in platelets originates from exosomes derived from prostate cancer. Therefore, measuring PCA3 in platelets from prostate cancer patients could be a promising method for cancer detection and staging (Bambace and Holmes 2011). There are many other platelet markers, highlighting the role of tumor-derived platelet markers in clinical diagnosis and their significant research potential in the field of tumor-regulated platelets across different domains.

Application of targeted therapy in platelets with cross-regulation of tumors
Tumors communicate with platelets through sEVs (exosomes), which transmit cancer markers and activate platelets in a CD63-dependent manner. Studies have shown that the uptake of sEVs from cancer cells treated with anti-CD63 antibodies is reduced by 75%. Platelet activation is a direct result of sEVs being taken up via CD63 (Dudiki et al. 2023). This finding suggests that CD63 is a highly attractive target for interventions aimed at tumor-mediated platelet activation in cancer patients and represents a potential therapeutic strategy worthy of further investigation. As the understanding of the mechanisms by which platelets contribute to tumor progression deepens, treatment strategies targeting platelets and their associated signaling pathways show promising clinical application prospects. Currently, interventions targeting the platelet-mediated tumor metastasis process primarily include antiplatelet aggregation drugs, platelet-derived growth factor receptor (PDGFR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, and platelet membrane-coated nanoparticles (Safdar et al. 2024; Guan et al. 2016). These strategies effectively inhibit metastasis in various tumor models, and some have entered the clinical trial stage.

Conclusion and prospects

Some research progress has been made
The use of platelets in cancer diagnosis and monitoring is not a new concept. Elevated platelet counts and the platelet-to-lymphocyte ratio are often associated with higher incidence rates and poorer survival outcomes (Bailey et al. 2017a; Bailey et al. 2017b). Similarly, the mean corpuscular volume (MCV), a broad indicator of platelet turnover, is elevated in early-stage lung cancer, but interestingly, it does not increase in advanced stages (Sabrkhany et al. 2017). Despite their ease of measurement, these parameters can be highly variable and may be influenced by other inflammatory conditions (Gasparyan et al. 2011). The ability of platelets to isolate tumor-derived proteins from the bloodstream has led to research into whether changes in platelet protein content could serve as early cancer diagnostic markers. Platelet-derived RNA has been identified as a potential diagnostic indicator for various pathological conditions, including inflammation, sickle cell disease, acute myocardial infarction, and cancer (Raghavachari et al. 2007; Eicher et al. 2016). For example, studies have shown that NSCLC patients have significantly higher levels of ITGA2B in their platelets than controls do. ITGA2B, when combined with carcinoembryonic antigen (CEA) and staging, can serve as a survival predictor. Research indicates that Tumor-Educated Platelets(TEPs) ITGA2B is a promising marker that can improve the identification rate of stage I non-small cell lung cancer patients and differentiate between malignant and benign pulmonary nodules (Li et al. 2022).

Future research on the cross-field regulation of platelet function in tumors
On the basis of the scientific facts elaborated in many existing articles, there seems to be a dynamic balance among platelets. Taking the cross-domain regulation of the peripheral platelet count by tumors as an example (Fig. 5), tumor cells increase the number of peripheral platelets through pathways such as paracrine signaling, regulation by amino acid metabolites, and cytokine regulation. When the platelet count increases, disseminated intravascular coagulation (DIC) can occur via factors such as TGF-β, ADP, and PDGF, leading to a decrease in the platelet count. Moreover, tumor cells can also reduce the platelet count by directly inhibiting the bone marrow and secreting factors such as TGF-β and TNF-α. When the PLT decreases, the risk of bleeding in the body increases, which may trigger a negative feedback mechanism in the body to promote the activation of pathways that increase the PLT, thereby achieving a dynamic balance. The relationship between the remote regulation of platelet balance by tumors and disease progression may become a research direction in the future.
Despite their lack of nuclei and short lifespan, platelets are increasingly recognized for their ability to respond to various pathological stimuli. Recent technological advancements have enabled researchers to move beyond the basic analysis of platelet quantity and size, focusing instead on proteins or RNA as diagnostic tools. A key reason is that the protein and RNA profiles of platelets, which are altered by tumors, dynamically change across different types of cancer patients, even in the early stages of the disease. This variation highlights the potential of platelets as promising tools for diagnosis, prognosis, and possibly treatment, particularly in the search for new methods to combat malignant tumors.
Opportunities and challenges coexist. Although the tumor-promoting effect of platelets has been confirmed in ovarian cancer, pancreatic cancer, and lung cancer, and a high platelet count/activation is closely associated with poor prognosis, the progress of clinical trials combining antiplatelet drugs (such as P2Y12 inhibitors and GPVI inhibitors) with chemotherapy has been slow. This is mainly due to practical challenges in multiple dimensions, including safety, efficacy, study design, and clinical awareness.Chemotherapy itself is prone to inducing chemotherapy-induced thrombocytopenia (CIT), which increases the risk of bleeding. Antiplatelet drugs, in turn, further inhibit platelet function, creating a "double hit"—a potential risk to patient safety. Additionally, the field of cancer treatment currently focuses on innovative therapies like targeted therapy and immunotherapy, resulting in relatively low attention to the "off-label use of old drugs" for antiplatelet agents, as well as insufficient investment in funds and talent. This constitutes a limitation in the current medical field.
Our research group is dedicated to the study of tumors and platelets. To date, we have completed several studies, including PlateletBase (Luo et al. 2025), which fills the gap in comprehensive resources for platelet research; a "new classifier" for distinguishing benign and malignant pulmonary nodules (Zu et al. 2022); the analysis and diagnosis of lung cancer via metabolomics (Liang et al. 2024); the identification of the "dark matter" of platelets involved in the tumor microenvironment (Zhang et al. 2025); and the identification of high-risk groups for NSCLC via the FLNA gene (Zu et al. 2025), among others. While existing research has revealed the complex mechanisms by which tumors influence platelets, further exploration is needed to understand the molecular details and potential for personalized treatment. Future research should focus on the precise regulatory mechanisms of tumor-induced changes in platelets, the development of novel biomarkers, and the clinical translation of targeted therapies, aiming to overcome the challenges in diagnosing and treating malignant tumors.