Tumor-platelet cross talk in cancer: mechanisms, thrombotic risk, and translational opportunities

Abstract

Platelets are recognized as mediators of cancer progression, extending beyond hemostasis to influence tumor growth, metastatic dissemination, immune evasion, and thrombotic complications. Tumors remodel platelets through thrombocytosis and tumor cell–induced platelet aggregation, and locally through tumor microenvironment cues that reprogram platelet function. These changes enable platelets to shield tumor cells, support epithelial-mesenchymal transition, promote angiogenesis and vascular remodeling, and establish immunosuppressive niches that promote metastasis. Platelets also drive both venous and arterial cancer-associated thrombosis (CAT) through procoagulant platelet states, platelet-derived extracellular vesicles, and cross talk with the endothelium and innate immune pathways. Platelet RNA signatures and emerging proteomic/multiomic profiling show promise for cancer detection, classification, and treatment monitoring. Preclinical and translational studies suggest that antiplatelet strategies (eg, aspirin, purinergic receptor P2Y type 12 inhibition) can modulate metastatic and thromboinflammatory pathways, motivating platelet-targeted interventions that mitigate bleeding risk. This review synthesizes platelet-tumor cross talk, linking tumor progression with CAT and vascular events, and highlights emerging platelet-based biomarkers and therapeutic opportunities.

Introduction

Platelets are increasingly recognized as active regulators of cancer progression, extending far beyond their canonical roles in hemostasis and thrombosis.1, 2, 3, 4, 5, 6 Clinical observations linking paraneoplastic thrombocytosis and platelet hyperreactivity with poor outcomes across solid tumors first suggested a functional connection between platelets and tumor biology,1, 2, 3, 4 and subsequent studies showed that tumors can both increase platelet production and reprogram platelet activation and cargo in ways that support tumor growth and dissemination.^5,6 A central feature of this bidirectional cross talk is tumor cell–induced platelet aggregation (TCIPA), in which tumor cells activate platelets to promote platelet-tumor aggregate formation, thromboinflammatory signaling, vascular arrest, and metastatic spread.7, 8, 9, 10, 11, 12, 13, 14, 15 Beyond these intravascular effects, platelets also accumulate within tumors, where they interact with malignant, stromal, endothelial, and immune cells to remodel the matrix, alter vascular permeability, promote angiogenesis, support tumor-cell plasticity, and suppress antitumor immunity.16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 In this review, we discuss how tumors reprogram platelet biology and how platelets shape metastasis, thrombosis, and translational opportunities.42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53

Tumor-driven thrombocytosis and TCIPA

Although the strongest mechanistic evidence derives from preclinical studies, available clinical and translational data support the concept that many tumors induce a systemic state characterized by increased platelet production and heightened platelet reactivity (Figure 1). In patients, this is often reflected by tumor-associated (paraneoplastic) thrombocytosis and functionally reinforced by TCIPA. Paraneoplastic thrombocytosis, typically defined as a platelet count >450 × 10³/μL, is common in advanced malignancies, with reported prevalence ranging from 10% to 65% depending on tumor type.1, 2, 3, 4^,54, 55, 56, 57, 58 This pattern supports a bidirectional interaction in which tumors stimulate platelet production and platelets reciprocally support tumor progression.1, 2, 3, 4 A predominant proposed mechanism centers on tumor-derived interleukin-6 (IL-6), described in ovarian and intestinal colitis-associated tumors, which drives hepatic thrombopoietin (TPO) production and promotes megakaryocyte (MK) maturation and platelet biogenesis.⁵ In tumor-bearing mice, silencing IL-6 or TPO eliminates thrombocytosis and reduces tumor burden, underscoring the functional relevance of this axis.⁵ Further, in humans, tumor-derived granulocyte-macrophage colony-stimulating factor has also been linked to increased platelet production; however, whether inhibiting tumor-derived granulocyte-macrophage colony-stimulating factor alters platelet counts and/or tumor growth remains unclear.⁶

Figure 1.

Mechanisms of tumor-induced thrombocytosis and TCIPA. Conceptual overview of tumor-driven thrombopoiesis and tumor cell–induced platelet activation in cancer. Tumor cells activate platelets via coagulation-dependent mechanisms, including TF-initiated thrombin generation and PAR signaling, as well as coagulation-independent pathways involving soluble agonists, damage-associated molecular patterns, and direct receptor-ligand interactions. These processes culminate in TCIPA, leading to the formation of platelet-tumor aggregates that amplify thromboinflammatory signaling, protect tumor cells from shear stress and immune surveillance, and facilitate vascular arrest and metastatic dissemination. Refer to Table 2 for process-specific mechanistic detail and translational implications of the platelet-tumor interactions summarized in this figure. Figure created with biorender.com. dos Santos BG (2026) https://biorender.com/ag4iht3.

Beyond IL-6–driven TPO upregulation, cancer directly remodels MK biology at the morphological, transcriptional, and metabolic levels. In a breast cancer model (mouse mammary tumor virus-polyoma middle T antigen), tumor burden reduced MK number and size, disrupted polyploidization, and induced proinflammatory transcriptional changes reflected in platelet cargo and linked to enhanced tumor invasion and lung colonization.⁵⁹ In lymphoma, MK-derived cytokines, rather than platelets themselves, accelerated tumor progression despite platelet depletion in TPO-overexpressing mice.⁶⁰ In multiple myeloma, MKs colocalize with tumor cells in bone marrow (BM) niches and support growth through local IL-6 and tumor necrosis factor SF13 secretion, whereas myeloma-derived S100A8/S100A9 further expands the MK pool via toll-like receptor 4 (TLR4)–STAT5 signaling.^61,62 Malignancy can also reprogram MK metabolism through a glucose transporter 1–MYC proto-oncogene–glucose-regulated protein 75 signaling axis in MKs that primes platelets toward a prometastatic phenotype, an effect reversed by glucose-regulated protein 75 blockade.⁶³

Importantly, MK reprogramming is not uniformly protumorigenic. In lung carcinoma and melanoma, tumor burden expanded BM MKs and increased thrombospondin-1 transfer to platelets, functioning as a host antiangiogenic response that suppressed early tumor vascularization.⁶⁴ In bone metastatic prostate and breast cancer models, direct MK-cancer cell contact induced tumor cell apoptosis, and TPO-driven MK expansion reduced skeletal lesions, whereas TPO deficiency was associated with more aggressive metastasis.^65,66 Together, these studies show that cancer reshapes MK abundance, maturation, and function in ways that alter platelet phenotype and the BM immune microenvironment.

Platelets are increasingly recognized as a heterogeneous population composed of functionally distinct subsets that differ in granule content, receptor expression, activation state, and age, including procoagulant, aggregatory, and inflammatory phenotypes. Younger, RNA-rich platelets are generally more transcript-rich, translationally competent, and functionally reactive than older platelets, raising the possibility that tumor-driven thrombocytosis shifts the circulating pool toward more reactive platelet states.⁶⁷ In cancer, this heterogeneity is further amplified by tumor-driven reprogramming of MK subsets in the BM and direct conditioning of circulating platelets through tumor contact, including uptake of tumor-derived RNA, extracellular vesicles (EVs), and proteins.⁴⁹ As a result, platelet transcriptomic and proteomic profiles in cancer may reflect the composite signal of multiple tumor-educated platelet states rather than a uniform systemic response. Consistent with this concept, distinct platelet subsets have been linked to specific tumor-promoting functions, including procoagulant platelets that support immune evasion, programmed death-ligand 1 (PD-L1⁺) platelets that suppress antitumor immunity, and CD36-high platelets that enhance metastatic signaling.68, 69, 70 Defining these tumor-associated platelet states at higher resolution will be important for refining mechanistic models and platelet-based biomarker strategies.

Direct tumor-platelet contact can also trigger rapid platelet activation and aggregation, a process linked to malignant progression and metastasis. Platelets from patients with advanced pancreatic, breast, and ovarian cancer display heightened agonist responsiveness compared with platelets from healthy donors.⁷ This hyperreactive state likely reflects convergent effects of tumor-platelet contact, soluble mediators, EVs, and coagulation pathway activation. Beyond aggregation, enhanced platelet reactivity may also promote immune evasion by increasing degranulation, release of immunosuppressive mediators, and stabilization of platelet-tumor aggregates that shield tumor cells from immune attack.35, 36, 37^,40, 41, 42, 43, 44, 45, 46, 47, 48^,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 Whether specific platelet subsets disproportionately drive this hyperreactive phenotype remains an important unresolved question with therapeutic implications.

Direct physical interactions between tumor cells and platelets appear to be major upstream triggers of TCIPA and cancer-associated platelet activation. Multiple studies implicate the platelet receptors C-type lectin-like receptor 2 (CLEC-2),82, 83, 84, 85, 86 glycoprotein VI (GPVI),^83,87, 88, 89, 90 glycoprotein Ib,^84,91 Fc γ receptor IIa,⁹² and integrins αIIbβ3,93, 94, 95, 96, 97 and α6β1,⁹⁸ as well as adhesion molecules such as P-selectin^99,100 in binding tumor cell ligands such as podoplanin (PDPN), galectin 3, von Willebrand factor (VWF), fibrinogen, a disintegrin and metalloproteinase 9, and P-selectin glycoprotein ligand-1 (Figure 1). Collectively, these receptor-ligand axes promote platelet activation and stabilize platelet-tumor cell adhesion, establishing a prometastatic platelet cloak around circulating tumor cells (CTC).

However, the capacity of tumor cells to induce platelet activation and aggregation is not uniform across tumor types. Emerging data suggest that some tumor cells engage platelets efficiently, whereas others interact only weakly, indicating that TCIPA is context-dependent rather than a universal feature of CTCs. This variability may help explain why antiplatelet therapy shows inconsistent effects across experimental metastasis models, particularly during early seeding, and highlights the need to define the tumor- and platelet-specific determinants of these interactions.^{87,89,101,102}

Alongside contact-dependent mechanisms, soluble and coagulation-linked pathways also potentiate TCIPA amplification. A major driver is tissue factor (TF), a key initiator of the extrinsic coagulation cascade that is broadly expressed across tumor types and associated with adverse outcomes.8, 9, 10 Tumor TF promotes thrombin generation, which in turn activates platelets via protease-activated receptor 1 (PAR1) and PAR4, thereby strengthening platelet activation and adhesion to tumor cells.11, 12, 13, 14 In addition, TF-bearing tumor microvesicles can propagate systemic platelet activation and contribute to cancer-associated venous thromboembolism (VTE).¹⁵ Tumor cells can further activate platelets by producing and releasing ADP and thromboxane A₂ (TxA₂), which signal through platelet purinergic receptor P2Y type 1 (P2Y₁)/purinergic receptor P2Y type 12 (P2Y₁₂) and thromboxane-prostanoid receptor (TP), respectively.^14,103, 104, 105 Finally, apoptotic tumor cells can release high mobility group box 1, which engages platelet TLR4 to promote platelet activation and enhance tumor dissemination.¹⁰⁶

Importantly, tumor-platelet interactions do not solely activate platelets. In some contexts, they can also enable tumor-mediated platelet uptake (engulfment).29, 30, 31, 32^,107 For example, human A549 lung cancer cells can phagocytose platelets, recycle platelet-derived CD42a to the tumor cell surface, and thereby increase adhesion to the vascular endothelium.¹⁰⁷ More broadly, platelet internalization has been reported to transfer platelet mitochondria, lipids, RNA, and proteins to tumor cells, supporting stem-like features, proliferation, bioenergetic fitness, and redox capacity.29, 30, 31, 32

Altogether, these findings highlight how tumors exploit platelets at multiple levels by increasing platelet counts, priming platelet reactivity, inducing aggregation through contact-dependent and soluble/coagulation pathways, and, in some cases, co-opting platelet-derived components to create a systemic and local milieu that enhances tumor-cell survival, growth, and metastatic competence.

Platelets in the tumor microenvironment (TME)

Platelet entry into tumors remains incompletely understood, but available data support a stepwise process in which platelets arrest on activated tumor endothelium and then enter the stroma, where local signals promote their retention and activation. Hypoxia, platelet G protein-coupled receptor signaling, and adhesion pathways have all been implicated in this process, including vascular endothelial growth factor (VEGF) A/VWF, C-X3-C motif chemokine ligand 1 (CX3CL1), platelet-activating factor, P2Y₁₂/PAR signaling, and GPVI-dependent interactions.16, 17, 18, 19^,88,103,108

After arresting on the tumor vasculature, platelets can infiltrate the tumor stroma, where they are retained and further activated by local cues. In ovarian cancer and hepatocellular carcinoma, hypoxia increases tumor-cell release of ADP and CX3CL1, which promotes platelet infiltration by activation of platelet focal adhesion kinase and CX3CL1 receptor 1, thereby promoting tumor growth.^103,108 Moreover, hypoxia may also act indirectly by stimulating endothelial production of platelet-activating factor, further increasing platelet adhesion and retention at the tumor site.¹⁹ Platelet G protein–coupled receptor signaling also contributes, because platelet-specific deletion of Gαi2 and Gα13 in mice reduces both tumor growth and platelet infiltration by >90%, implicating P2Y₁₂ and PAR pathways in platelet entry into tumors.¹⁸ Consistent with these in vivo observations, under physiologically relevant shear stress in an ovarian TME on-chip, platelet infiltration into the tumor compartment requires GPVI binding to tumor galectin-3.⁸⁸ Despite these advances, it remains unclear whether platelet entry into tumors is predominantly driven by active, adhesion-dependent transendothelial trafficking or by passive extravasation through gaps in defective tumor vasculature, and also how this balance varies across tumor types. Resolving the relative contributions of these routes and the signals that govern platelet retention and persistence within stromal niches will be important for selectively targeting intratumoral platelet programs.

Once within the tumor stroma, platelets form direct contacts with tumor cells through receptors including CLEC-2, P-selectin, and integrin αIIbβ3.^18,84 These interactions activate platelets and promote the release of granules rich in proproliferative and proangiogenic mediators, thereby supporting tumor proliferation (Figure 2).^18,84 Activated platelets also release soluble growth factors such as epidermal growth factor (EGF), platelet-derived growth factor B (PDGFB), and pro–transforming growth factor-β (TGF-β), which further support tumor-cell proliferation and survival.33, 34, 35, 36, 37, 38 Beyond paracrine signaling, platelet-tumor cross talk can also rewire tumor metabolism, because tumor cells can acquire platelet mitochondria, thereby shifting metabolism toward glycolysis, reducing reactive oxygen species, and enhancing proliferation and invasiveness in breast cancer and osteosarcoma models.30, 31, 32 Finally, in prostate cancer, platelets have been reported to contain and, according to 1 study, synthesize testosterone, which may be released upon tumor cell–induced platelet activation and promote androgen receptor signaling.³⁹

Figure 2.

Contribution of platelets to tumor growth and metastasis. Within the TME, platelets infiltrate tumor tissue and interact with endothelial cells, stromal cells, immune cells, and tumor cells. Platelet-derived factors remodel extracellular matrix architecture, promote pathological angiogenesis, and regulate vascular permeability, facilitating tumor growth and dissemination. In parallel, platelets suppress antitumor immunity through soluble mediators, immune checkpoint engagement, metabolic reprogramming, and physical cloaking of tumor cells, thereby impairing T cell, NK cell, and myeloid cell effector functions. These local platelet-driven processes also contribute to premetastatic niche formation by recruiting leukocytes and conditioning distant tissues to support metastatic seeding. Figure created with biorender.com. dos Santos BG (2026) https://biorender.com/amj1afk.

These tumor-local effects extend beyond the primary lesion, as platelets also contribute to premetastatic niche formation. By releasing tumor-derived and platelet-derived mediators, platelets can remodel distant stromal programs, recruit myeloid cells, and condition secondary sites for tumor seeding.109, 110, 111, 112, 113, 114 For example, platelet-derived C-X-C motif chemokine ligand (CXCL) 5/CXCL7 signaling promotes granulocyte recruitment around platelet-tumor aggregates, whereas CXCL12 helps recruit C-X-C motif chemokine receptor (CXCR) 4⁺ progenitor and angiogenic cells.^113,114

Beyond niche conditioning, sustained platelet-tumor interactions within the TME directly promote tumor-cell plasticity and invasive behavior (Figure 2). A central program is epithelial-mesenchymal transition (EMT), which enhances the migratory and invasive capacity of tumor cells. In highly vascularized tumor regions, cancer cells often display enhanced EMT signatures, consistent with the idea that sustained exposure to blood-borne cues, including platelet contact, may promote this transition.115, 116, 117 Mechanistically, platelet adhesion and activation can engage tumor-cell pathways such as NF-κB, TGF-β, and Wnt–β-catenin, inducing EMT-associated transcriptional programs (eg, Snail1 and vimentin).^117,118 Platelets may reinforce EMT through metabolic cross talk, because mitochondrial transfer increases glycolysis, boosts ATP production, and enhances reactive oxygen species detoxification in metastatic osteosarcoma and breast cancer models.30, 31, 32 In addition, uptake of platelet-derived EVs containing 12-lipoxygenase enables colon cancer cells to synthesize 12S-hydroxyeicosatetraenoic acid, further promoting EMT and metastatic competence.¹¹⁹ These findings establish platelets as active participants in the TME, contributing to metabolic reprogramming, proliferation, and invasive plasticity at the primary site while conditioning distant organs for metastatic seeding.

Platelets and tumor angiogenesis

Platelets are now recognized as regulators of tumor angiogenesis and vessel maturation, although evidence for this role is derived mainly from in vitro systems and mouse models and still requires validation in human tumors and clinical cohorts. Because oxygen and nutrient diffusion restrict avascular tumor nodules to ∼1-2 mm³, neovascularization is required for tumor expansion and to provide vascular routes for invasion, intravasation, and metastatic spread.²⁰ Tumor-associated vessels are abnormal and highly permeable, exposing subendothelial matrix (eg, collagen) and increasing endothelial adhesion ligands such as VWF, which promote platelet recruitment and activation.^21,22 Activated platelets release granule cargo that shapes angiogenic programs within the TME, including α-granule–derived proangiogenic mediators (VEGF, basic fibroblast growth factor, and endothelial cell growth factor) and growth factors such as EGF, TGF-β, and platelet-derived growth factor.21, 22, 23, 24 Importantly, platelet cargo is compartmentalized across granule subsets, enabling stimulus-selective secretion of proangiogenic vs antiangiogenic factors.^25,120,121 In vitro, signaling through ADP-P2Y₁₂ receptor preferentially promotes VEGF release, whereas activation via TxA₂ favors secretion of antiangiogenic mediators such as endostatin and platelet factor 4.^120,121 Consistent with this, platelets exposed to the MCF-7 breast cancer cell line preferentially secrete VEGF over endostatin, suggesting that tumors can bias platelet activation toward a proangiogenic secretory profile.²⁵

Platelets also amplify angiogenesis indirectly through microparticles and soluble mediators that increase endothelial proangiogenic programs and mobilize BM-derived proangiogenic cells.^26,27 In addition, platelet release of hematopoietic cytokines can expand BM output and mobilize proangiogenic cells.²⁸ In melanoma models, platelet α-granule release of IL-6, VEGF, and stromal cell–derived factor 1α promotes recruitment of CXCR4⁺ BM-derived cells to hypoxic tumor vessels, supporting angiogenesis and tumor growth.²⁸

Beyond promoting neovascularization, platelets can also stabilize tumor vessels and limit intratumoral hemorrhage. In lung and melanoma tumor models, transfusion of platelets from healthy donors reverses tumor hemorrhage induced by platelet depletion and enhances tumor growth.¹²² This vascular protection has been attributed to platelet release of angiopoietin-1, serotonin, and PDGFB, which promote endothelial maturation, recruit pericytes and vascular smooth muscle cells, and support extracellular matrix deposition.122, 123, 124 By preserving vessel integrity, platelets help sustain perfusion and nutrient delivery, supporting the metabolic demands of rapidly proliferating tumors.

Beyond angiogenesis, platelets facilitate metastatic dissemination by promoting vascular arrest and extravasation of CTCs. Platelet-tumor microaggregates protect tumor cells from shear stress and immune clearance while enhancing adhesion to the endothelium under flow.^17,100,113,125, 126, 127 Platelets then promote transendothelial migration by disrupting endothelial barrier integrity, in part through δ-granule ATP release and additional mediators such as TxA₂, serotonin, CXCL5/CXCL7, and autotaxin-lysophosphatidic acid signaling.^111,128, 129, 130, 131 Together, these pathways link platelet-driven vascular dysfunction to efficient metastatic seeding at distant sites (Figure 2).

Platelet-mediated tumor immune modulation

Platelets actively modulate antitumor immunity through direct interactions with leukocytes and tumor cells, as well as the release of soluble mediators and EVs. The preclinical data discussed further show that these platelet-derived signals shape immune recruitment and effector function in the TME and the circulation, often favoring immune suppression and metastatic competence (Figure 2).

T cells

Platelet-immune cross talk in cancer has been examined across multiple leukocyte lineages, but the strongest mechanistic evidence to date centers on platelet–T-cell interactions. Platelets can suppress antitumor T-cell immunity through both stromal remodeling that limits intratumoral T-cell access and direct inhibitory signaling that dampens effector function.

One stromal mechanism involves platelet-derived PDGFB, which activates cancer-associated fibroblasts, increases extracellular matrix deposition and interstitial hypertension, and thereby restricts T-cell infiltration into tumors.^40,132, 133, 134 Platelets also directly restrain T-cell responses via TGF-β, which is released from α-granules and activated by thrombin-dependent cleavage of glycoprotein A repetitions predominant. Active TGF-β promotes regulatory T-cell differentiation while suppressing IL-2 and interferon γ production by CD8⁺ T cells, and inhibition of this pathway can reprogram the TME toward immune activation and reduce tumor growth and metastasis.35, 36, 37

Additional platelet-derived mediators further attenuate T-cell immunity. Platelet-derived TxA₂ suppresses T-cell receptor signaling through rho guanine nucleotide exchange factor 1, limiting CD8⁺ T-cell proliferation, differentiation, and effector cytokine production.^40,81 Platelet-derived EGF and serotonin have also been shown to suppress intratumoral CD8⁺ T-cell function, whereas depletion of platelet serotonin enhances antitumor immunity and improves response to programmed cell death protein 1 blockade in preclinical models.^41,71 Finally, platelets can directly contribute to checkpoint-mediated suppression via PD-L1. Platelet PD-L1 engages programmed cell death protein 1 on T cells and can be acquired from tumor cells, and platelet depletion or platelet-specific PD-L1 deletion reduces tumor growth while increasing intratumoral activated CD8⁺ T cells.^42,43 Together, these findings identify platelets as multifaceted suppressors of antitumor T-cell immunity.

NK cells

Platelets impair Natural killer (NK) cell–mediated tumor surveillance through both soluble immunoregulatory signals and contact-dependent shielding (platelet cloaking) of tumor cells. Platelet-derived TGF-β downregulates NK cell activating receptors, including natural killer group 2D and natural killer p30, and platelet PD-L1 may further contribute to checkpoint-mediated inhibition.35, 36, 37^,42,43 Platelet coating of tumor cells promotes shedding of major histocompatibility complex class I polypeptide-related sequence A/B, transfer of platelet-derived major histocompatibility complex class I, and, in the case of platelet-derived regulator of G-protein signaling 18 (RGS18), engagement of the inhibitory HLA-E–CD94–natural killer group 2A axis, thereby limiting CTC recognition by NK cells and favoring metastatic escape.44, 45, 46^,135

B cells

Evidence for platelet regulation of B-cell antitumor immunity remains limited. In a colorectal cancer metastasis model, platelet/MK Erbin was identified as a negative regulator of B-cell–mediated immune control, as Erbin deficiency reprogrammed B-cell metabolism, enhanced cytotoxic T-cell responses, and reduced metastatic dissemination.⁴⁷ These findings suggest that platelet metabolic signals can influence B-cell–dependent antitumor immunity.

Myeloid cells

Beyond platelet-lymphocyte cross talk, platelets also shape myeloid composition and phenotype within primary and metastatic tumor niches. Platelet TGF-β promotes polarization of tumor-associated macrophages toward an M2-like, immunosuppressive state, whereas prostagladin E₂ signaling through E prostanoid receptor (EP) 2 and EP4 similarly suppresses immune activation by impairing oxidative phosphorylation in M1-like macrophages.35, 36, 37^,48 Platelet-leukocyte interactions also contribute to myeloid recruitment, as selectin-dependent signaling can activate endothelium to induce C-C motif chemokine ligand 5 and promote monocyte recruitment into permissive metastatic niches.⁷²

Platelets also reprogram neutrophil responses in cancer. Circulating platelet-neutrophil aggregates define a neutrophil state enriched for degranulation, chemotaxis, and transendothelial migration and are associated with worse prognosis.⁷³ Platelets also promote formation of neutrophil extracellular trap in NETosis through P-selectin–glycoprotein ligand-1 and platelet TLR4–extracellular signal-regulated kinase 5 signaling, driving CTC capture, metastasis, and thromboinflammation.74, 75, 76, 77 Consistent with this, elevated circulating citrullinated histone H3 predicts VTE and all-cause mortality in patients with cancer.^78,79,82,83 Intratumoral platelet-neutrophil aggregates have also been linked to vascular occlusion, necrosis, and perinecrotic EMT, further supporting the platelet-neutrophil axis as a therapeutic target.⁸⁰ Together, these findings show that platelets promote immunosuppressive macrophage polarization, monocyte recruitment, and neutrophil reprogramming toward prometastatic and prothrombotic states.

Platelets and thrombosis in cancer

Building on the concept of cancer-induced platelet priming described previously, this section highlights how these qualitative shifts in platelet behavior promote a prothrombotic state and contribute to cancer-associated thrombosis (CAT). Clinically, CAT encompasses VTE as well as arterial thromboembolism (ATE) events (most commonly myocardial infarction and ischemic stroke), with population-level reviews estimating cancer-associated VTE rates on the order of ∼4% to 20% and arterial event rates of ∼2% to 5%, and more recent syntheses emphasizing that ATE risk is meaningfully elevated in cancer.^136,137 Consistent with this phenotype, platelets from patients with advanced/metastatic malignancy can exhibit broad agonist hyperreactivity, supporting the concept of a systemically primed platelet state in cancer. A comprehensive list of platelet-derived mediators and surface molecules implicated in cancer progression and associated thrombosis is provided in Table 1 and Table 2.

Table 1.

Platelet-derived mediators and surface-associated molecules in cancer

Location	Name	Function	References
α-Granules	PDGFB	Promotes matrix remodeling, metastasis, and angiogenesis; maintains vascular integrity	123
	TGF-β	Mediates immunosuppression; promotes tumor progression	35
	Fibrinogen	Supports tumor cell survival; increases platelet adhesion and aggregation; enhances metastatic potential	11
	EGF	Increases vascular permeability; promotes cell growth, proliferation, and angiogenesis	22,34
	VEGF	Increases vascular permeability; promotes angiogenesis	21,22
	bFGF	Promotes mitosis and angiogenesis	21,23
	IL-6	Promotes tumor progression and angiogenesis	28
	IL-8	Stimulates cell migration and proliferation; promotes angiogenesis	22
	MMP-9	Degrades matrix; promotes angiogenesis and metastasis	22
	HGF	Promotes tumor cell growth, proliferation, and angiogenesis	22
	Ang-1	Anti-inflammatory; maintains vascular integrity; promotes angiogenesis	122, 123, 124
	P-selectin	Facilitates tumor cell–platelet–leukocyte interactions; promotes platelet aggregation and thrombosis	99
	CXCL5/7	Promotes granulocyte recruitment and metastasis	113
	SDF-1	Promotes tumor progression, metastasis, and angiogenesis	28,114
	Endostatin	Inhibits angiogenesis and tumor growth	25,120,121
	PF4	Inhibits angiogenesis and tumor growth	121
δ-Granules	ADP	Promotes platelet activation	22
	ATP	Increases vascular permeability; promotes metastasis	128,129
	Serotonin	Enhances platelet activation; maintains vascular integrity; promotes angiogenesis	22,122
Cell membrane	αIIbβ3	Promotes platelet adhesion and aggregation	100
	CLEC-2	Promotes platelet adhesion, activation, and aggregation	84
	PD-L1	Immune checkpoint ligand; regulates tumor growth; promotes immune evasion	42,43,71
	ADAM10/ADAM17	Promotes immune evasion; enhances metastatic potential	45
	GP1b-IX-V	Promotes cell adhesion and metastasis	126
	MHC class I	Evades immune surveillance	135
Lipid mediator	LPA	Enhances tumor cell migration and invasion	130,131
	TxA2	Supports tumor progression and metastasis	81

ADAM, a disintegrin and metalloproteinase; Ang-1, angiopoietin-1; bFGF, basic fibroblast growth factor; GP1b-IX-V, glycoprotein 1b-IX-V; HGF, hepatocyte growth factor; LPA, lysophosphatidic acid; MHC, major histocompatibility complex; MMP-9, matrix metalloproteinase-9; PF4, platelet factor 4; SDF-1, stromal cell-derived factor 1.

Table 2.

Summary of platelet-tumor mechanisms in preclinical and clinical studies

Mechanism	Key molecules	Experimental models	Clinical evidence	Platelet heterogeneity context	Translational implications	References
Paraneoplastic thrombocytosis	IL-6, TPO, GM-CSF	Mouse models of ovarian and colitis-associated cancer	Thrombocytosis in 10% to 65% of patients with cancer; IL-6–driven TPO in ovarian/GI tumors; thrombocytosis predicts poor prognosis across multiple cohorts of patients with cancer	Systemic MK expansion; downstream platelet subset effects unresolved	TPO/IL-6 pathway as therapeutic target; platelet count as a potential prognostic biomarker	1, 2, 3, 4, 5, 6
Cancer-induced MK reprogramming	IL-1α/β, TNF, STAT5, GLUT1-MYC-GRP75, TSP-1	Mouse models of MMTV-PyMT, LLC, melanoma, and myeloma	Increased BM MKs in patients with metastatic breast cancer; MK expansion in patients with MPN	Protumor vs host-protective MK subsets; tumor-specific MK reprogramming may generate distinct platelet subsets	Targeting MK-derived cytokines (IL-1α/β, TNF) or metabolic nodes (GRP75, GLUT1-MYC axis); scRNA-seq to map BM MK heterogeneity in distinct tumors	59, 60, 61, 62, 63, 64, 65, 66,138
TCIPA: platelet receptor–tumor ligand interactions	CLEC-2/PDPN, GPVI/galectin-3, GP1b/VWF, αIIbβ3/fibrinogen, α6β1/ADAM9, FcγRIIa, P-selectin/PSGL-1	Mouse models of melanoma, osteosarcoma, breast, ovarian, prostate, and lung cancer	Hyperreactive platelets detected in patients with late-stage pancreatic, breast, and ovarian cancer	Each platelet population highly expressing a specific receptor may mark a functionally specialized subset that binds tumor cells expressing distinct ligands	Receptor-targeted antiplatelet strategies (eg, CLEC-2, GPVI blockade); TCIPA assays as functional ex vivo biomarkers	7,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98
TCIPA: coagulation-linked activation	TF/thrombin/PAR1-4, TF+ EVs, ADP/P2Y12, TxA2/TP, HMGB1/TLR4	Mouse models of HCC, fibrosarcoma, pancreatic, and ovarian cancer	Tumor TF expression correlated with grade and prognosis in pancreatic, breast, and urological cancers; TF+ EVs elevated in patients with CAT	Thrombin activates PS+ procoagulant platelets, amplifying platelet-tumor aggregates	Tumor TF targeting to prevent TCIPA; TF+ EV quantification for CAT risk	8, 9, 10, 11, 12, 13, 14, 15,103, 104, 105, 106
Platelet infiltration of the TME	VEGF-A/VWF axis, ADP/CX3CL1, FAK, CX3CR1, PAF, Gαi2/Gα13, GPVI/galectin-3	Mouse models HCC, melanoma, breast, and ovarian cancer	Intratumoral platelets observed in HCC, NSCLC, Lung ADC, PDAC, gastric and breast tumor human specimens	Intratumoral retention may select for activated, granule-releasing platelet subsets	Targeting FAK, CX3CR1, P2Y12, or GPVI to restrict platelet tumor extravasation	16, 17, 18, 19,88,103,108
Paracrine tumor support and premetastatic niche formation	TGF-β, EGF, PDGFB, bFGF, VEGF, CXCL5/7/CXCR2, SDF-1/CXCR4, androgens, LPA, MMP1	Mouse models of melanoma, osteosarcoma, ovarian, breast, prostate, and colon cancer	Clinical data correlates high circulating androgens and TGF-β levels with prostate and ovarian cancer advanced stage	Stimulus-selective α-granule release (eg, P2Y12 receptor-VEGF release); CD36-high subset drives PDGFB-mediated breast cancer lung metastasis	Platelet-specific PDGFB/TGF-β blockade to reduce CAF activation; CXCR2 blockade to limit priming of new metastatic niche	23,33, 34, 35, 36, 37, 38, 39,70,109, 110, 111, 112, 113,132, 133, 134
Platelet-tumor metabolic cross talk	Mitochondrial transfer, 12-lipoxygenase/12-HETE, GRP75, platelet lipid/RNA transfer, EMT induction	Mouse models of osteosarcoma, colon, and breast cancer	No human validation to date	Distinct platelet subsets may differ in mitochondrial content and transfer capacity	GRP75 inhibition; 12-LOX pathway blockade (12-HETE/EMT axis); mitochondrial transfer as novel therapeutic vulnerability	29, 30, 31, 32,117, 118, 119
Platelet-driven tumor angiogenesis	VEGF, bFGF, ECGF, EGF, TGF-β, PDGF, endostatin, PF4, Ang-1, IL-6, SDF-1α; P2Y12 vs TxA2 secretory bias; platelet-derived microparticles	Mouse models of melanoma, breast, and lung cancer	Tumor cell–induced, compartmentalized release of proangiogenic and antiangiogenic factors from human platelets demonstrated ex vivo	P2Y12 activation biases toward VEGF release; TxA2 biases toward endostatin/PF4; tumors may shift balance toward proangiogenic platelet profile	P2Y12 inhibition or TxA2 modulation to reduce secretion of angiogenic factors	20, 21, 22, 23, 24, 25, 26, 27, 28,120, 121, 122, 123, 124
CTC cloaking, vascular arrest, and extravasation	δ-Granule ATP/P2Y2/Munc13-4, LPA/autotaxin/LPAR1, TxA2, serotonin, CXCL5/7, CD61 transfer, GPIbα, αIIbβ3, CLEC-2	Mouse models of melanoma, osteosarcoma, and breast cancer	No human validation to date	Procoagulant and aggregatory subsets cooperate in CTC shielding; CD61 platelet–tumor cell transfer enhances endothelial adhesion	P2Y2/Munc13-4 axis as novel therapeutic to reduce CTC extravasation	42,44,45,82,85, 86, 87,89,90,98,125, 126, 127, 128, 129, 130, 131,139
Platelet suppression of T cell immunity	TGF-β/GARP/thrombin, TxA2/ARHGEF1/RhoA–ROCK–PTEN, serotonin/serotonylation, EGF, PD-L1/fibronectin-1/α5β1/GP1bα	Mouse models of melanoma, pancreatic, colon, and breast cancer	Platelet PD-L1 detected and predicts immunotherapy response in patients with NSCLC.	PD-L1+ platelet subset transfers PD-L1 to tumor cells	GARP/thrombin blockade; COX-1 inhibition to restore T-cell cytotoxicity; platelet PD-L1 as a complementary prognostic biomarker	35, 36, 37,40, 41, 42, 43,71,81
Platelet suppression of NK cell immunity	ADAM10/ADAM17–MICA/MICB shedding, MHC-I transfer, RGS18/HLA-E–CD94–NKG2A, fibrinogen/αIIbβ3, P-selectin, CLEC-2	Mouse models of melanoma, LLC, leukemia, and breast cancer	No human validation to date	RGS18-expressing platelets activate inhibitory HLA-E–CD94–NKG2A axis on NK cells	ADAM10/17 and NKG2A blockade to enhance NK cytotoxicity; platelet NKG2D-ligand shielding as actionable target	44, 45, 46,135
Platelet–B-cell metabolic cross talk	Erbin-mitochondria axis, acyl-carnitine release, OXPHOS reprogramming, PD-1 degradation in B cells	Mouse model of colorectal carcinoma	No human validation to date	Platelet Erbin regulates mitochondrial OXPHOS and acyl-carnitine release that reprograms B cell metabolism	Platelet Erbin as potential target for combination immunotherapy	47
Platelet–myeloid cell cross talk	TGF-β/M2 polarization, PGE2/EP2–EP4, P-selectin/PSGL-1/NETosis, TLR4-ERK5, CCL5/monocyte recruitment, citrullinated H3, PNA	Mouse models of LLC, pancreatic, and breast cancer	PNA transcriptomic signature independently predicts worse prognosis in human cancers; elevated citrullinated H3 predicts VTE and all-cause mortality; tumor vascular occlusion by PNA demonstrated	P-selectin+ subset drives PSGL-1-dependent NETosis; platelet TLR4-ERK5 axis activated by surgical stress promotes NET-mediated CTC capture	P-selectin/PSGL-1 blockade; platelet TLR4 inhibition to reduce NET-driven metastasis; PNA transcriptomic signature as prognostic immune biomarker for solid tumors	48,72, 73, 74, 75, 76, 77, 78, 79, 80
CAT	PS exposure/procoagulant platelets, PEVs, TF/thrombin/PAR, CLEC-2/PDPN, sP-selectin, D-dimer, citrullinated H3	Mouse models of melanoma, glioma, and DLBCL	PS+ platelets linked to hypercoagulability in colon cancer; PEVs elevated in DLBCL; sP-selectin predicts VTE (Vienna/CATS, HR 2.5); PDPN correlates with VTE in glioma	PS-exposing procoagulant platelet subset is key effector; PEVs expand procoagulant surface area; CLEC-2–expressing platelets activated by tumor/stromal PDPN	Platelet phenotyping (PS exposure, sP-selectin) to refine CAT risk stratification; CLEC-2/PDPN blockade for VTE prevention	136,137,140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155

ADAM, a disintegrin and metalloproteinase; ADC, adenocarcinoma; ARHGEF1, rho guanine nucleotide exchange factor 1; bFGF, basic fibroblast growth factor; CAF, cancer-associated fibroblast; CATS, Cancer and Thrombosis Study; CD36, cluster of differentiation 36; COX-1, cyclooxygenase-1; CRC, colorectal cancer; CX3CR1, CX3CL1 receptor 1; DLBCL, diffuse large B-cell lymphoma; ECGF, endothelial cell growth factor; FAK, focal adhesion kinase; FcγRIIa, Fc gamma receptor IIa; GRP75, glucose-regulated protein 75; GLUT1, glucose transporter 1; GARP, glycoprotein A repetitions predominant; GM-CSF, granulocyte-macrophage colony-stimulating factor; GI, gastrointestinal; HETE, hydroxyeicosatetraenoic acid; HCC, hepatocellular carcinoma; HMGB1, high mobility group box 1; LLC, Lewis lung carcinoma; LOX, lipoxygenase; LPAR1, lysophosphatidic acid receptor 1; MDSC, myeloid-derived suppressor cell; MICA/MICB, MHC class I polypeptide-related sequence A/B; MHC-I, MHC class I; MMP, matrix metalloproteinase; MMTV-PyMT, mouse mammary tumor virus-polyoma middle T antigen; MPN, myeloproliferative neoplasm; NET, neutrophil extracellular trap; NKG2A, natural killer group 2A; NSCLC, non–small cell lung cancer; NKG2D, natural killer group 2D; OXPHOS, oxidative phosphorylation; PAF, platelet-activating factor; PD-1, programmed cell death protein 1; PDAC, pancreatic ductal adenocarcinoma; PDGF, platelet-derived growth factor; PEVs, platelet extracellular vesicles; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PNA, platelet-neutrophil aggregates; PSGL-1, P-selectin glycoprotein ligand-1; RCT, randomized controlled trial; RhoA, Ras homolog family member A; ROCK, Rho-associated coiled-coil containing protein kinase; scRNA-seq, single-cell RNA sequencing; SOPs, standard operating procedures; SSRI, selective serotonin reuptake inhibitor; SDF-1α, stromal cell-derived factor 1α; sP-selectin, soluble P-selectin; STAT5, signal transducer and activator of transcription 5; TEP, tumor-educated platelet; TNF, tumor necrosis factor; TSP-1, thrombospondin-1; UPR, unfolded protein response.

At the effector level, cancer primes platelets to exhibit procoagulant activity, accelerating thrombin and fibrin generation. A key mechanism is the emergence of a phosphatidylserine (PS) exposing platelet subpopulation, which provides a catalytic surface for assembly of intrinsic tenase and prothrombinase complexes, markedly amplifying thrombin generation. PS-rich platelet microparticles/EVs can further expand this procoagulant surface area. In patients with colon cancer, increased PS exposure on platelets and microparticles has been linked to heightened procoagulant activity, aligning platelet membrane remodeling with hypercoagulability in vivo.¹⁴⁰

TF is a central trigger of CAT, particularly when expressed by tumor cells or released on TF⁺ EVs, which trigger thrombin generation and amplify platelet activation and clot growth.^141,142 In parallel, CLEC-2–PDPN signaling contributes to thrombosis in cancer, as PDPN on tumor or stromal cells activates platelets through CLEC-2, and disruption of this axis reduces VTE in experimental models.^143,144 Together, these pathways link hemostatic activation to malignant progression.

Beyond mechanistic insights, platelet phenotypes and platelet-derived biomarkers may help refine VTE and possibly ATE risk stratification in cancer, which currently relies mainly on clinical variables and coagulation markers such as D-dimer. In CAT, platelet EVs are elevated in diffuse large B-cell lymphoma and other malignancies,145, 146, 147 and high tumor PDPN expression has been independently associated with increased VTE risk in glioma.¹⁴⁸ Whether markers of CLEC-2 activation, PS-exposing platelets, or platelet EV signatures add value for thrombosis prediction or longitudinal monitoring remains unclear. Among platelet-centered biomarkers, soluble P-selectin is the best validated. In the Vienna Cancer and Thrombosis Study cohort, levels ≥53.1 ng/mL independently predicted VTE, and incorporation of soluble P-selectin with D-dimer into the Vienna-modified Khorana score was prospectively validated.^149,150 Thus, platelet-derived biomarkers may provide clinically useful information beyond existing scores, although the evidence is stronger for VTE than for ATE. Clinical adoption is currently limited by assay variability, the lack of standardized measures of platelet activation, and the absence of prospective studies evaluating these biomarkers for serial monitoring or risk-guided intervention strategies. Still, these findings support biomarker-focused studies to improve thrombosis prediction, particularly in patients with intermediate risk.151, 152, 153

Targeting platelet-tumor interactions: therapeutic opportunities

Platelets support tumor cell survival in circulation, immune evasion, extravasation, and metastatic niche formation, making antiplatelet therapy an attractive translational strategy. However, because platelets are also critical for vascular integrity, perioperative hemostasis, and tissue repair, the clinical use of aspirin- and P2Y₁₂-based approaches will likely be context dependent and must be weighed against bleeding risk, wound-healing concerns, and treatment interruptions around procedures common in cancer care.

Aspirin

Low-dose aspirin is thought to act in platelet-tumor biology primarily by inhibiting platelet cyclooxygenase-1 and TxA₂ generation, thereby reducing platelet activation and support to CTCs. Preclinical studies suggest that aspirin can inhibit EMT, limit metastatic niche formation, and relieve TxA₂-dependent suppression of antimetastatic T-cell immunity.^81,156, 157, 158 In patients, however, the benefit appears context-dependent. The aspirin after completion of standard adjuvant therapy for colorectal cancer trial did not improve recurrence outcomes in unselected colorectal cancer, whereas the Swiss group for clinical cancer research 41/13 and aspirin for localized advanced stage colorectal cancer with alreted PI3K pathway trials suggest greater benefit in molecularly defined subgroups, particularly tumors with PI3K-pathway alterations such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutations.159, 160, 161 Ongoing studies, such as Add-Aspirin, will help define how broadly these findings extend across tumor types.¹⁶²

P2Y₁₂ inhibitors

Because the ADP-P2Y₁₂ axis is central to platelet amplification and aggregate stability, P2Y₁₂ inhibition is an attractive strategy to blunt TCIPA and platelet-associated thromboinflammation. In preclinical models, P2Y₁₂ blockade reduces both thrombosis and metastatic burden, and in the ticagrelor-oncology study, ticagrelor reduced spontaneous platelet activation and large tumor cell–induced platelet aggregates in patients with metastatic cancer.^163,164 These findings support clinical feasibility, although definitive oncological end points remain largely untested and periprocedural management may be more challenging than with aspirin.

Emerging platelet-directed strategies

Platelet-based delivery platforms

Beyond inhibiting platelet function, an emerging translational strategy is to exploit platelets themselves, or platelet membrane–mimetic nanoparticles, as delivery vehicles for cancer therapeutics.165, 166, 167 Preclinical studies show that engineered platelets can deliver checkpoint inhibitors to postsurgical tumor beds and CTCs, whereas platelet membrane-coated nanoparticles can enhance delivery of chemotherapeutic and chemophotothermal payloads to tumors.165, 166, 167, 168, 169 These approaches repurpose platelet adhesive and tumor-tropic properties for therapeutic delivery, but the field remains preclinical and faces challenges in manufacturing, drug loading, payload stability, and avoidance of unintended platelet activation, thrombosis, and off-target effects.

Receptor-targeted antiplatelet approaches

Beyond aspirin and P2Y₁₂ inhibition, other platelet-directed approaches may also have translational potential, particularly agents targeting receptor-ligand interactions more directly implicated in platelet-tumor cross talk, such as CLEC-2, GPVI, integrin α6β1, or P-selectin.^82,89,99 Although these strategies remain largely preclinical, they may offer a more selective means of disrupting tumor cell–induced platelet activation and metastatic spread.

Platelet-derived biomarkers

Tumor cells reshape platelet molecular cargo through altered thrombopoiesis, uptake of tumor- and stromal-derived factors, and changes in platelet RNA processing, including alternative splicing. Early studies showed that platelet mRNA profiles can distinguish cancer from controls and, in some settings, capture tumor type and molecular features, establishing platelets as a potential liquid biopsy source.⁴⁹ Subsequent work expanded classifier development, including a multicancer study reporting detection of 18 cancer types with high specificity in asymptomatic controls.⁵⁰ Platelet RNA classifiers have since been described in non–small cell lung cancer, myeloproliferative neoplasms, breast cancer, and ovarian cancer, with some incorporating spliced RNA features to capture tumor-associated platelet states.51, 52, 53^,170 Many incorporate spliced RNA features, leveraging the retained platelet spliceosome to capture tumor-associated activation states.^49,171 However, biological and preanalytical confounders, including altered platelet turnover, ex vivo activation, and leukocyte contamination, remain important limitations.^172,173 Clinical translation will require rigorous standardization, external validation, and demonstration of generalizability across diverse patient populations.174, 175, 176, 177

Complementing platelet transcriptomics, platelet proteomics is an emerging area suggesting that cancer can alter platelet protein cargo with potential diagnostic relevance. Early studies in lung, pancreatic, and ovarian cancer identified distinct platelet proteomic changes and proposed candidate biomarker panels.^178,179 Platelet proteomes may also reflect treatment exposure, as anticancer therapy has been associated with measurable proteomic remodeling.¹⁸⁰ Additional studies, including in myeloproliferative neoplasms, further support cancer-type–specific platelet protein alterations while highlighting the need for external validation.^181,182 Clinical translation will require larger, well-phenotyped cohorts, rigorous control of confounders, and independent external validation.

Challenges and future directions

Several barriers must be addressed before platelet-based diagnostics and therapies can be integrated into oncology. Platelet RNA and protein signatures are highly sensitive to preanalytic variables, host inflammatory states, cardiovascular comorbidities, and anticancer therapy, limiting attribution to tumor burden alone and raising concerns about generalizability. Accordingly, clinical translation will require standardized workflows, clinically relevant comparator cohorts, and prospective external validation.¹⁷⁷

Therapeutic benefit is also likely to vary by tumor type, stage, and molecular subtype, underscoring the need for predictive biomarkers to guide patient selection and limit unnecessary bleeding risk.^183,184 In addition, platelets can exert both tumor-promoting and tumor-restraining effects, arguing against indiscriminate inhibition and in favor of strategies that selectively target pathogenic platelet states.^87,124,185, 186, 187, 188 Future progress will likely depend on biomarker-guided trials, rational combination strategies, and more selective agents targeting platelet-tumor pathways with limited roles in physiological hemostasis, such as CLEC-2 or integrin α6β1.82, 83, 84, 85, 86^,98,189,190

Conclusion

Platelets are now recognized as active drivers of cancer progression, far beyond their traditional roles in hemostasis and thrombosis. By reprogramming platelet production, activation, and cargo, tumors co-opt platelets to remodel the TME, promote angiogenesis and metastasis, and suppress antitumor immunity. Notably, many of these same platelet-dependent pathways also contribute to CAT, positioning platelets at the intersection of tumor progression and thromboinflammation. Platelet omics offers a promising, minimally invasive window into tumor biology, but its clinical translation will require rigorous standardization, robust validation, and biomarker-guided therapeutic development. Together, these advances may establish platelet biology as both a mechanistic framework and a translational avenue in cancer.

Conflict-of-interest disclosure: The authors declare no competing financial interests.