Tumor treating fields alter local coagulation dynamics in glioblastoma patients

Glioblastoma (GBM) is a highly aggressive brain tumor, associated with hypercoagulability and thrombosis. Tumor Treating Fields (TTFields), a non-invasive therapy that uses low-intensity, alternating electric fields to disrupt cancer cell division, prolongs survival when used concomitantly with radiochemotherapy. TTFields-treated patients often exhibit distinct recurrence patterns, suggesting a local interaction between TTFields and tumor-associated coagulation, underlying mechanisms remain unclear. This study examined coagulation profiles in TTFields-treated patients' blood, tumor cells, and plasma-derived extracellular vesicles using molecular, hemostaseologic, and phenotypic analyses. Our findings revealed that short-term TTFields exposure significantly prolongs blood coagulation in GBM patients and healthy donors by altering tissue factor (TF) expression and disrupting the extrinsic coagulation pathway. TTFields reduced clot rigidity by decreasing Factor II/FXIII activity and platelet count, without impairing fibrinogen function. Patient-derived GBM cells exposed to TTFields exhibited increased TF abundance. RNA-based microarray analysis of GBM cells confirmed coagulation-related changes, including upregulation of platelet adhesion marker ITGA2, and downregulation of THBS1, a regulator of clotting, platelet aggregation, extracellular matrix remodeling, and tumor invasiveness. Additionally, TXNIP, a coagulation-modulating gene, was downregulated after TTFields exposure, indicating a link to immune regulation in the tumor microenvironment. In an allogeneic co-culture model of patient-derived GBM cells and peripheral blood, TTFields modulated coagulation and immune responses, likely by rebalancing pro- and anticoagulant factors in the tumor microenvironment, reducing the prothrombotic state, and altering inflammatory pathways. These findings provide insights into how TTFields influence coagulation and, eventually, immune regulation, offering strategies to optimize clinical decision-making and mitigating thromboembolic complications in GBM patients.