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. 2026 Sep 22;16:1951597. doi: 10.3389/fonc.2026.1951597

Figure 1.

Illustration of the molecular mechanisms linking tumor-derived factors, bone marrow platelet production, and tumor-educated platelet (TEP) function in cancer. Arrows indicate the influence of tumor cells and microenvironmental signals on alternative splicing and transcriptome reprogramming in platelets, facilitating mRNA, protein, and lipid transfer. Central pathway shows circulation of TEPs, their interaction via P-selectin/PSGL-1, and involvement in stemness, EMT, angiogenesis, metastasis, and immune evasion, with key signaling axes and cell types labeled.

Platelet education by tumor cells and the mechanisms of tumor-educated platelets in cancer. Tumor cells and the tumor microenvironment release systemic factors, including interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet factor 4 (PF4), and kynurenine. These signals act on hematopoietic stem/progenitor cells (HSPCs) and megakaryocytes in the bone marrow, regulating megakaryocyte differentiation, maturation, thrombopoiesis, the selective loading of RNAs and proteins into nascent platelets. Tumor cells release extracellular vesicles, RNAs, ncRNAs, proteins, lipids, and DNA into the circulation. These components can be internalized and stored by platelets, allowing platelets to acquire tumor-associated molecular information. Platelets retain pre-mRNAs, spliceosomes, snRNAs, and associated splicing proteins. Tumor-derived signals may trigger alternative splicing and transcriptomic reprogramming, thereby modifying platelet RNA cargo and functional status. Tumor-derived extracellular vesicles, soluble factors, inflammatory cytokines, coagulation factors, and other tumor microenvironmental signals collectively influence platelet phenotype and function. Through these mechanisms, naïve platelets are educated into tumor-educated platelets (TEPs). TIMP mRNA in TEPs promotes tumor cell proliferation whereas TPM3 mRNA in TEPs promote tumor cell metastasis. Platelet P-selectin binds to PSGL-1 on breast cancer stem cells, activates WNT-FRIZZLED signaling and β-catenin stabilization, and further induces NANOG/OCT4/SOX2-mediated stemness, TWIST/SNAIL/VIMENTIN-associated epithelial-mesenchymal transition (EMT), and the VEGF–VEGFR2 feed-forward axis-associated invasiveness and metastasis. TEP-derived VEGF, EGF, bFGF, PDGF-B, and angiopoietins can promote tumor angiogenesis, facilitate vessel stabilization via the PDGF−B/PDGFRβ signaling axis, and drive the recruitment of tumor-associated macrophages (TAMs), further amplifying the release of matrix metalloproteinases (MMPs) and pro-angiogenic cytokines. GARP−TGF−β signaling, which mediates the suppression of NK cells and cytotoxic T lymphocytes (CTLs) and promotes the generation of regulatory T cells (Tregs), myeloid−derived suppressor cells (MDSCs), and M2−polarized TAMs, together with circulating tumor cells (CTCs) that acquire a platelet−mimetic MHC−I phenotype, collectively shape an immune−evasive tumor microenvironment.