Heparin and synthetic heparin mimetics – Do they act as potential immunomodulators in an in vitro metastatic context?

Introduction Thrombosis represents a frequently underestimated risk and a major cause of mortality in metastatic tumor diseases, which is at least partly due to the activation of platelets by cancer cells. Low molecular weight heparin (LMWH) is a guidline-based anticoagulant used in thromboprophylaxis and treatment of cancer patients. The ongoing debate on whether heparin exerts anti-tumorigenic effects beyond anticoagulation is further complicated by the heterogeneous structure of heparin as a natural product. To address this issue and to enable structure-activity relationship (SAR) analyses, synthetic non-glycosidic heparin mimetics have been developed in the form of copolymers of sodium 4-styrenesulfonate and itaconic acid with molecular masses between 10 and 20 kDa [ 1 ] [ 2 ]. This project focuses on platelet-tumor cell interactions and platelet-mediated immune regulation, which has not yet been thoroughly investigated. The central question is how tumor-activated platelets induce immunosuppressive activities and whether heparin derivatives are capable of reconstituting immune balance, with a particular focus on CD4 + and CD8 + T cells. Method Platelet-derived immunosuppressive mediators (TGF-β, PF-4, MMP2) were examined using the following methods: MMP2 activity assay to evaluate the effect of synthetic heparin mimetics (250 µg/ml) compared to clinically relevant concentrations of commercial heparins. Flow cytometry to assess TGF-β-mediated differentiation of CD4 + cells into immunosuppressive regulatory T cells and to investigate the impact of heparin mimetics of varying molecular masses. SAW biosensor measurements to determine binding affinities of heparins and mimetics to TGF-β. Fondaparinux was included as a reference compound. ELISA techniques to address the release of cytolytic cytokines (granzyme B and perforin) from CD8 + T cells. Results Synthetic heparin mimetics showed clear superiority in inhibiting MMP2 activity, whereas commercial heparins at therapeutic concentrations had no measurable effect. In the analysis of TGF-β-mediated CD4 + T cell differentiation, copolymers with lower molecular mass attenuated the rate of differentiation, suggestion an immune-activating effect. This observation was confirmed by fondaparinux. Binding affinity measurements using the SAW biosensor largely supported these findings, demonstrating relevant interactions of heparin and mimetics with TGF-β. Furthermore, the synthetic mimetics displayed significantly lower binding affinity to PF-4 compared to unfractionated heparin (UFH), which may indicate a reduced susceptibility to HIT II. The impact of TGF-β1 on reducing the release of cytolytic perforin and granzyme B from CD8 + T cells is reversed by heparin and mimetics in different intensities, favoring smaller molecular sizes. Conclusion In summary, LMWH and heparin mimetics can reverse the immunosuppressive activities of platelets and thus provide a novel immuno-oncological perspective for their application in oncology. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany