The interplay between platelets and CTCs is primarily mediated by direct surface receptor binding and by extracellular proteins that facilitate receptor bridging (Fig. 2). Building on the previous study of Erpenbeck and Schön (22), the adhesive mechanisms underlying platelet-CTC crosstalk were refined, clearly revealing the physical basis of their interaction. Key mechanisms include: i) the engagement of platelet C-type lectin-like receptor 2 (CLEC-2) with Podoplanin expressed on tumor cells, which induces platelet activation and facilitates tumor cell metastasis (6); ii) the interaction of the platelet glycoprotein (GP) Ib-IX–V complex with tumor cells via von Willebrand factor (vWF), mediating adhesion (22); iii) platelet GPIIb/IIIa (αIIbβ3 integrin) binding to ligands such as fibrinogen and vWF, enhancing platelet-tumor cell aggregation (23–25); iv) metastatic potential is augmented by platelet GPVI receptor interactions with galectin-3, collagen, or fibrin on tumor cells (26,27); v) integrin αvβ3 on tumor cells binding to the Arg-Gly-Asp (RGD) sequence, promoting adhesion (28); vi) the activation of protease-activated receptors (PAR) on tumor cells by thrombin, enhancing their interaction with platelets (22); vii) integrin α6β1 binding to ADAM9 on tumor cells, promoting metastasis (29); viii) platelet-derived acidic sphingomyelinase (Asm) inducing p38K phosphorylation in tumor cells, thereby activating integrin α5β1 and facilitating adhesion and metastasis (30,31); and ix) P-selectin on the surface of platelets binds to sialyl Lewis^x (SLe^x) on the surface of CTCs (22,32). This complex subsequently interacts with endothelial P-selectin, resulting in CTCs rolling and vascular retention (22,32). Collectively, these molecular interactions represent potential therapeutic targets for cancer treatment.

Platelets confer critical protective effects on CTCs during metastasis (Fig. 3A). First, platelets bind to CTCs through glycan-lectin interactions (such as CLEC-2, galectins) to form a ‘protective shield’ (21,33). This interaction helps CTCs evade the damaging effects of fluid shear stress by promoting thrombus formation (34). Furthermore, it enables CTCs to escape immune surveillance, particularly the cytotoxic effects of natural killer cells, thereby significantly enhancing CTC survival within the circulation (4,35,36). Hemodynamic analysis indicates that rolling CTCs induce local vortex formation, which may potentiate platelet recruitment to the CTC surface (37). Upon adhesion, platelets enhance CTC stabilization at endothelial sites by reducing cellular motility and mitigating mechanical constraints through physical encapsulation (37). Additionally, shear forces exhibit positive correlation with platelet density during adhesive events, while CTC arrest propensity inversely correlates with cellular size and stiffness. By contrast, platelet rigidity demonstrates negligible influence on adhesion efficacy (37).

Secondly, platelet adhesion to CTCs is facilitated through surface adhesion molecules, including P-selectin, CLEC-2 and GPIIb/IIIa. This interaction promotes CTC-endothelial adhesion and vascular retention, establishing critical prerequisites for metastatic colonization in distant organs (38–41). A previous study by Schlesinger (41) summarized the role of platelet receptors in tumor metastasis, which advanced our comprehension of platelet-CTC adhesion. Notably, surgical stress induces TLR4-dependent ERK5 phosphorylation, resulting in GPIIb/IIIa integrin activation and subsequent platelet-CTC aggregation (42). These aggregates exhibit enhanced entrapment by neutrophil extracellular traps, thereby promoting their retention within the pulmonary microvasculature (42). Heparanase released from α-granules cooperates with P-selectin to enhance platelet adhesion and promote thrombogenicity, facilitating metastasis (43). Furthermore, tissue factor (TF)-induced coagulation facilitates the coating of CTCs by platelets, leading to the formation of circulating tumor microemboli (CTM) (44).

Additionally, platelets secrete multiple bioactive mediators that collectively facilitate metastatic progression. The platelet release contains TGFβ, ATP, and serotonin, which, in combination with matrix metalloproteinases (MMPs) and histamine, synergistically enhance tumor cell invasiveness, increase vascular permeability, and promote extravasation and metastatic niche formation (45–49). For example, TGFβ released via platelet-CTC crosstalk can activate the metastatic capacity of CTCs by triggering metabolic reprogramming and bioenergetic adjustment (50). On the other hand, TGFβ activates the TGFβ/Smad pathway, inducing SERPINE1/PAI-1 expression to activate PI3K/AKT signaling, thereby enhancing CTC metastatic competence (51). Molecular analyses reveal that platelet-CTC crosstalk upregulates key oncogenic pathways in CTCs, including MYC, IL33, VEGFB, PTGER2, PTGS2 and TGFβ2 expression profiles (52). Regulation of angiogenesis is a key mechanism in tumor progression, with extensive evidence indicating that platelets directly contribute to this process, likely through factors released upon their activation (53). Ghosh et al (54) developed an angiogenesis-enabled tumor microenvironment (TME) chip that recapitulates multicellular interactions among tumor cells, endothelial cells and platelets in ovarian cancer, providing direct evidence of platelet-mediated angiogenesis enhancement. Furthermore, platelets orchestrate immune-modulatory functions through chemokine release (particularly CXCL7 and CXCL5 from α-granules), facilitating immune cells' recruitment and pre-metastatic niche establishment (55,56).

Platelets significantly facilitate EMT during the dissemination of CTCs via diverse molecular mechanisms (57). TGFβ secreted by platelets triggers EMT by activating both TGFβ/Smad and NF-κB signaling pathways (46). Furthermore, platelet-derived growth factor-D (PDGF-D) promotes EMT by upregulating transcriptional regulators such as Twist1 and Notch1 in colorectal cancer cells, as well as interacting with PDGFRβ in tongue squamous cell carcinoma cells, thereby inducing phosphorylation of key kinases including p38, AKT and ERK (58,59). Platelets also secrete lysophosphatidic acid (LPA), which binds to LPA receptors on tumor cells to enhance their invasive and migratory capacities (57,60). Additionally, platelet-derived microvesicles modulate EMT-associated gene expression in tumor cells through the transfer of regulatory RNAs, including mRNA and microRNA (miRNA) (61). Building on Wang et al's (57) detailed delineation of platelet-induced EMT signaling pathways, the present review integrates recent advances to provide a more comprehensive mechanistic overview. For instance, platelets contribute to CTC plasticity by maintaining a mesenchymal phenotype during circulation, enabling more efficient transition to an epithelial state upon reaching distant metastatic sites. This epithelial-mesenchymal plasticity augments tumor cell invasiveness and metastatic potential (52). These multifaceted roles establish platelets as critical mediators of cancer metastasis and provide a mechanistic basis for therapeutic strategies targeting platelet-CTC crosstalk. However, while current research predominantly focuses on platelet-mediated EMT in CTC generation, few investigations address how platelets support CTC colonization via mesenchymal-epithelial transition (MET) in distant organs.

Emerging evidence demonstrates a complex bidirectional interplay between platelets and tumor cells (7) (Fig. 3B). This interaction induces platelet activation, phenotypic transformation and transcriptomic reprogramming, culminating in the formation of tumor-educated platelets (TEPs). TEPs are characterized by their capacity to sequester and enrich tumor-specific substances (including proteins, nucleic acids, EVs) during their interaction with tumors, leading to distinct alterations in DNA, RNA and protein expression profiles (62). A recent study has demonstrated that platelets actively internalize DNA-containing EVs and membrane-free DNA fragments, thereby sequestering tumor-derived DNA (63). These platelets play pivotal roles in tumor growth, angiogenesis and metastasis (41). Through interaction with cancer cells, platelets are ‘educated’ and carry tumor-related biological information (64). Due to the short lifespan and enclosed membrane structure, TEPs provide real-time molecular snapshots of tumor activity; therefore, they are regarded as promising indicators for cancer detection and disease monitoring (65).

The tumor-induced platelet education process operates through several critical aspects. Firstly, tumor cells initiate platelet aggregation via direct binding to platelet surface receptors or through extracellular protein-mediated bridging, which is known as ‘tumor cell-induced platelet aggregation’ (TCIPA) (33). In metastatic models, TCIPA formation occurs within 1 min of tumor cell intravasation, shielding tumor cells from immune attacks and facilitating tumor growth and metastasis (33,56,66). Beyond inducing TCIPA, Strasenburg et al (66) elucidated multiple mechanisms of tumor-mediated platelet activation, substantially expanding our understanding of this process. Secondly, tumor-derived factors, including thrombopoietin and interleukin-6, stimulate megakaryopoiesis and platelet generation in bone marrow, leading to paraneoplastic thrombocytosis, a well-established poor prognostic indicator across multiple malignancies (67). Furthermore, tumor cells trigger platelet degranulation, releasing immunosuppressive (for example, CD40L) and procoagulant (for example, TF) mediators that reshape the TME (68,69). Elevated tumor TF expression initiates the coagulation cascade, inducing platelet activation and fibrin production. The resulting fibrin mediates TCIPA and enhances adhesion of CTM to the mesothelium, ultimately promoting polyclonal metastasis (70). Fibrinogen, upon conversion to fibrin, may form a matrix scaffold that influences the recruitment of immune cells, mediates inflammatory responses, stimulates angiogenesis, and increases vascular permeability, collectively facilitating the development of a pre-metastatic niche that supports tumor progression (71). Collectively, tumor cells orchestrate the function and quantity of platelets through multiple mechanisms, establishing a microenvironment conducive to tumor development and metastasis (72).

Extensive preclinical and clinical evidence demonstrates that common antiplatelet agents, including aspirin, clopidogrel and c7E3/ReoPro, exert significant antitumor effects (99). The multifaceted mechanisms of aspirin include: Direct suppression of tumor cell proliferation, inhibition of platelet-CTC crosstalk, and attenuation of platelet-derived pro-angiogenic and growth factors, cytokines and chemokines (100). Notably, aspirin may exert anticancer properties through non-COX-dependent pathways, including the inhibition of inflammatory processes and the induction of apoptosis, as well as the suppression of signal transduction mediated by IκB kinase β and ERK (99,101). In 2016, the U.S. Preventive Services Task Force endorsed low-dose aspirin for cancer prevention in selected populations (aged 50–69 years), albeit with the caveat that its benefits may be offset by the risk of major bleeding (102,103).

In addition to aspirin, other antiplatelet agents also exhibit significant roles in cancer therapy. Preclinical studies demonstrated the therapeutic potential of P2Y₁₂ inhibitors (for example, clopidogrel and ticagrelor) in disrupting platelet-tumor interactions, thereby inhibiting cancer cell migration and metastasis (104–106). Experimental models demonstrate that ticagrelor and EP3 antagonist DG-041 inhibit platelet-induced phenotypic changes in colon cancer cells (106). Such changes include the downregulation of E-cadherin, upregulation of Twist1, enhanced cell motility and increased platelet aggregation (106).

Some antiplatelet agents inhibit platelet-CTC crosstalk by targeting specific platelet surface receptors. Notably, multiple surface proteins, including GPVI, CLEC-2, GPIIb/IIIa, etc., represent validated therapeutic targets for attenuating tumor progression and metastasis (107). For instance, GPIIb/IIIa antagonists (for example, eptifibatide) have demonstrated efficacy in inhibiting cancer cell metastasis both in vitro and in animal models (108,109). Furthermore, activated GPIIb/IIIa receptors serve as dual-function targets for molecular imaging probes, enabling tumor visualization, and chemotherapeutic agents, facilitating precise therapeutic delivery (110,111). GPVI blockers (for example, revacept) reduce thrombosis by disrupting platelet-collagen interactions and concurrently block platelet-induced EMT and COX-2 expression in cancer cells (112). Targeting podoplanin on CTCs selectively inhibits the binding of CLEC-2 receptors on platelets to podoplanin, thereby preventing platelet-mediated tumor protection (113). Additionally, inhibitors of GPIbα and P-selectin exhibit potential in preclinical studies for inhibiting the interaction between platelets and cancer cells (39,114). Several published reviews have summarized various antiplatelet agents for cancer therapy, synthesizing fragmented findings in the field and further advancing the understanding of targeting platelets for cancer treatment (78,107). Based on current advances, integrating antiplatelet agents into comprehensive therapeutic strategies, such as in combination with chemotherapy or targeted therapy, may enhance efficacy through complementary mechanisms.

Engineered platelet technologies represent a promising paradigm for cancer therapy, leveraging fabrication techniques such as drug loading, genetic engineering and membrane modification to create intelligent drug delivery systems. Concerning the combination therapy with chemotherapeutic agents, two principal strategies have been established. Firstly, the incorporation of doxorubicin (DOX) into platelets significantly enhances therapeutic efficacy against lymphoma (Fig. 4A) (115). Secondly, small EVs derived from platelets can be exploited to encapsulate DOX, subsequently facilitating targeted delivery to CTCs (Fig. 4B) (116). An innovative approach involves disrupting CTC clusters through platelet-CTC crosstalk; loading platelet decoys or lyophilized platelets with tissue-type plasminogen activator facilitates dissociation of these clusters, thereby inhibiting metastatic potential (117). Within the domain of genetic engineering, a study by Li et al (118) utilized lentiviral vector-mediated transduction of hematopoietic stem cells to generate platelets expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (Fig. 4D). These engineered platelets substantially reduced hepatic metastasis in a prostate cancer mouse model while preserving native hemostatic function (118). Collectively, these advancements not only enhance treatment specificity but also minimize off-target effects.

Furthermore, engineered platelets represent a promising platform for integration with tumor immunotherapy, enabling novel therapeutic strategies. One approach utilizes engineered platelets as carriers for immune checkpoint blockade. Surface conjugation of anti-PD-L1 antibodies onto platelets leverages their inherent tumor tropism, facilitating targeted accumulation within post-resection inflammatory niches (119). Upon activation, platelets release microparticles encapsulating anti-PD-L1 antibodies, which block the PD-L1/PD-1 interaction between tumor cells and T cells, consequently reversing immunosuppression and potentiating T cell-mediated antitumor responses (Fig. 4C) (119). Engineered platelets can also augment chimeric antigen receptor T (CAR-T) cell therapy. Surface-anchored anti-PD-L1 antibodies obstruct the PD-1/PD-L1 pathway, preventing CAR-T cell exhaustion, while activated platelets secrete cytokines such as IL-15 to enhance CAR-T cell proliferation and activity (120). Additionally, platelet-derived microparticles and chemokines enhance CAR-T cell infiltration into tumors (120). Beyond immune modulation, a distinct strategy involves loading engineered platelets with cytotoxic complexes, such as granzyme B and perforin, enabling immune-independent cytotoxicity against CTCs through mechanisms mimicking T cell effector functions, thereby inhibiting metastasis (121). These strategies enhance therapeutic efficacy synergistically when combined with chemotherapy or immunotherapy.

However, research on engineered platelets as carriers for radiosensitizers remains limited but promising; targeted tumor delivery improves radiotherapy efficacy while sparing normal tissues (122,123). In vitro megakaryocyte cultures provide platelets for engineering, yet scaling clinical-grade, donation-independent production requires overcoming yield and quality barriers (124).

Nanotechnology demonstrates significant potential in modulating platelet-CTC crosstalk. For instance, perfluorocarbon nanoparticles inhibit platelet activation, thereby enhancing T cell infiltration into tumors and improving immunotherapy efficacy (125). Similarly, chlorogenic acid nanoparticles also suppress platelet activation, disrupting the tumor vascular barrier to augment chemotherapeutic drug permeability (126). Additionally, nanoparticles functionalized with activated platelet membranes target CTC-associated microthrombi, significantly reducing lung metastasis in a breast cancer model (Fig. 4E) (127). Photodynamic nanostrategies enable the release of nitric oxide, which suppresses platelet activation by downregulating the expression of P-selectin and blocking the activated configuration of GPIIb/IIIa (128). This intervention not only reduces tumor-derived procoagulant factors secretion but also avoids hemorrhagic risks associated with systemic anticoagulation. Collectively, these approaches provide a novel therapeutic paradigm for inhibiting tumor metastasis through precise platelet function modulation.

Several nanostrategies disrupt platelet-CTC crosstalk without direct targeting. For example, MMP2-responsive polymer-lipid-peptide nanoparticles encapsulate DOX and an anti-platelet antibody R300 (129). Upon MMP2 activation in the TME, the release of R300 induces platelet micro-aggregation and depletion, which facilitates vascular permeabilization and DOX delivery for enhanced anticancer efficacy (129). Furthermore, strategies focusing on adhesion disruption include CD44-targeted DOX-loaded liposomes that incorporate the Lys-Leu-Val-Phe-Phe (KLVFF) peptide motifs that self-assemble into nanofiber networks on CTC surfaces, physically impeding platelet aggregation (130). By blocking platelet-CTC crosstalk, such approaches effectively suppress tumor invasion and metastasis. These nanotechnological innovations illustrate promising avenues for cancer therapy, offering novel insights for developing precise and efficient treatment strategies.

Beyond the aforementioned strategies, substantial advancements have been achieved in direct approaches specifically targeting CTCs. An intelligent nano-diagnostic system was developed for targeting CTCs of metastatic breast cancer (131). This nano-diagnostic system is composed of targeted multi-responsive nanomicelles encapsulating near-infrared fluorescent superparamagnetic iron oxide nanoparticles, featuring dual-mode imaging and dual toxicity. It tracks and eliminates CTCs before colonization at distant sites, thereby impeding metastatic progression (131). Furthermore, CTCs exhibit unique functional properties that render them ideal targets for personalized drug sensitivity testing. In vitro isolation and culture of CTCs, followed by pharmacological screening, can predict patient-specific therapeutic responses, mitigating the risk of ineffective or adverse treatments (132).